Gross total resection of pituitary adenomas after endoscopic vs. microscopic transsphenoidal surgery: a meta-analysis

Abstract

Background

Microscopic transsphenoidal surgery (mTSS) is a well-established method to address adenomas of the pituitary gland. Endoscopic transsphenoidal surgery (eTSS) has become a viable alternative, however. Advocates suggest that the greater illumination, panoramic visualization, and angled endoscopic views afforded by eTSS may allow for higher rates of gross total tumor resection (GTR). The aim of this meta-analysis was to determine the rate of GTR using mTSS and eTSS.

Methods

A meta-analysis of the literature was conducted using PubMed, EMBASE and Cochrane databases through September 2016 in accordance with PRISMA guidelines.

Results

Seventy case series that reported GTR rate in 8257 pituitary adenomas patients were identified. For all pituitary adenomas, eTSS (GTR=74.0%; I²=92.1%) was associated with higher GTR as compared to mTSS (GTR=66.4%; I²=84.0%) in a fixed-effect model (P-interaction<0.01). For functioning pituitary adenomas (FPAs) (n=1,170 patients), there was no significant difference in GTR rate between eTSS (GTR=75.8%; I²=63.9%) and mTSS (GTR=75.5%; I²=79.0%); (P-interaction=0.92). For non-functioning pituitary adenomas (NFPAs) (n=2,655 patients), eTSS (GTR=71.0%; I²=86.4%) was associated with higher GTR as compared to mTSS (GTR=60.7%; I²=87.5%) in a fixed-effect model (P-interaction<0.01). None of the associations were significant in a random-effect model (all P-interaction>0.05). No significant publication bias was identified for any of the outcomes.

Conclusion

Among patients who were not randomly allocated to either approach, eTSS resulted in a higher rate of GTR as compared to mTSS for all patients and for NFPA patients alone, but only in a fixed-effect model. For FPA, however, eTSS did not seem to offer a significantly higher rate of GTR. These conclusions should be stated with caution because of the nature of the included non-comparative studies.

Introduction

The transsphenoidal approach to the sellar region was first developed for resection of sellar pathology by Schoffler in 1907 and later popularized by Cushing without the aid of lens magnification [14, 17, 60, 77]. Introduction of the operating room microscope for transsphenoidal surgery by Jules Hardy in 1960s greatly improved intra-operative visibility and surgical outcomes [13, 40, 60]. Since around the turn of the 21^st century, the introduction of the endoscope have allowed for improved illumination and panoramic visualization of the anterior skull base, with many skull base centers rapidly adopting this new technology [14, 46].

Despite this, the choice between endoscopic transsphenoidal surgery (eTSS) and microscopic transsphenoidal surgery (mTSS) remains controversial in the neurosurgical community, and no head-to-head study has compared the two approaches in terms of efficacy or safety. Whereas mTSS requires either a sublabial incision or removal of the nasal septum, eTSS is most frequently performed transnasally with some disruption of the nasal anatomy [43, 57]. Perhaps as a result, some studies have showed that mTSS could also be associated with longer hospital stay postoperatively compared to eTSS [36]. On the other hand, the majority of endoscopic approaches utilize 2 dimensional endoscopic lens and are associated with a considerable learning curve [3, 12, 49, 58]. Some experts have also claimed that eTSS operations may last longer or result in higher rate of post-operative cerebrospinal fluid (CSF) leak than mTSS [66, 79]. Overall, no true consensus exists and many factors play may a role in choosing either of the modalities. Patient care could be improved by a more uniform practice and more objective comparative data.

With regard to surgical outcomes, gross total resection (GTR) remains of key importance, particularly for functioning adenomas. The presence of residual disease can necessitate adjuvant medical therapy, radiosurgery and place the patient at a greater future risk of visual decline or pituitary dysfunction. Although previous systematic reviews and meta-analyses have failed to show a significant difference in GTR for pituitary adenoma resection using either mTSS or eTSS [1, 36, 76, 81], we set out to update the estimated pooled rate of GTR after each method and to identify which patient and tumor-related factors were associated with higher rates of GTR.

Methods

Search Strategy and Paper Selection

A systematic review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies reporting GTR in patients harboring pituitary adenomas in the PubMed, Embase, and Cochrane databases [65]. A search strategy was designed in consultation with a librarian, using relevant keywords for identification of articles reporting both approaches (Appendix 1).

All databases were searched on July 25, 2017 and duplicates were removed. All articles were screened for title and abstract relevance by two authors, independently, to identify articles reporting GTR for mTSS, eTSS, or both. Discrepancies in study selection were resolved by discussion and consultation with a senior author. Selected articles were subject to full-text screening. Only articles that reported GTR specifically for pituitary adenomas were included. Case reports, commentaries, abstracts, reviews, animal studies, studies with an endoscopically-assisted approach or extended approach, studies in pediatric patients (<18 years old), re-operations, and cadaveric studies were excluded. Only literature in English was reviewed.

Data Extraction

Study characteristics were extracted from the full text of selected studies including authors, publication year, country of origin, sample size, study design, and duration of study. Patient characteristics were extracted including number, sex, age, type of pituitary adenomas (non-functioning pituitary adenomas [NFPA] vs. functioning pituitary adenomas [FPA]), histological type, number of macroadenomas, number of microadenomas, surgery type, and rate of GTR.

Meta-Analysis

Data analysis was performed using Comprehensive Meta-Analysis (CMA) version 3 (Copyright 1998–2014. Biostat, Inc.). The fixed-effect model using the inverse variance method was used to obtain the overall rate and the 95% confidence intervals. The random-effects model that accounts for the within- and the between-study variances according to the method of DerSimonian and Laird was also used for comparison [25]. Pooled rate estimates of GTR together with 95% confidence intervals were used to assess the efficacy of transsphenoidal surgery among patients with any pituitary adenoma, FPA, and NFPA [25]. Heterogeneity was evaluated among studies by using Cochran’s Q test (P<0.10) and I² percentage. An I² value >50% was considered to be high [41]. Potential sources of heterogeneity were explored using sub-group analyses by categorical covariates: surgery type (eTSS; mTSS), tumor type (FPA vs. NFPA), continent (Asia, Australia, Europe, North America, South America), center (single vs. multiple), surgeon (single vs. multiple), male percent (high, defined as ≥ median value of 50%, vs. low <50 %), age in categories (25–35, 36–40, 41–50, 51–55, 56–60 and 61–65), study design (cohort; case series), microadenoma (low percent, defined as < median percent; high percent defined as ≥ median percent); macroadenoma (low percent; high percent), FPA type (ACTH-producing, GH-producing, and prolactinoma), and publication after 2000. It is important to note that the p-interaction resulting from the subgroup analyses should be interpreted with caution because the original studies are case series and comparing two groups of studies based on a specific covariate will not resolve all the other potential differences among the studies being compared. Meta-regression was conducted on continuous covariates including international journal impact factor and year of publication. Publication bias was assessed using funnel plots, Egger’s linear regression test, and Begg’s and Mazumdar rank correlation test. If publication bias was identified, the number of missing studies was evaluated by the trim-and-fill method. A P-value <0.05 was considered significant except where otherwise specified.

Results

Search Results

The systematic search resulted in 1641 articles after duplicates were removed. After title and abstract screening, 1514 articles were excluded, resulting in 127 articles for full text evaluation. After full-text screening, a total of 57 case series were included in the meta-analysis, with a total of 7,896 patients that had undergone surgery for a pituitary adenomas (Figure 1, Appendix 2) [4–11, 15, 16, 18–23, 27, 30–33, 35, 37–39, 42, 44, 45, 47, 48, 50–56, 59, 64, 68–71, 74, 75, 78, 80, 82–84, 86–92]. The median percentage of males was 53.0% (range: 0–72.2%). Mean age per study ranged from 31.6 to 63.5 years (median of means=50.0 years) (Table 1). The median percentage of macroadenomas was 86.25% (Table 2, Appendix 3). The median percentage of FPA was 47.28% (range: 0–100%).

Figure 1.

Flowchart: Study Selection process of the identified studies

Table 1.

Characteristics of Studies Included in the Analysis of Gross Tumor Resection (GTR)

Study	Year of Publication	Study Design	Prospective	Country	Duration of Study	Surgical Intervention	Single Center	Single Surgeon
Bodhinayake et al.4	2014	CS	no	USA	2006 – 2011	ETSS	yes	yes
Bokhari et al.5	2013	CS	no	Australia	July 1998 – September 2010	ETSS	yes	yes
Campbell et al.6	2010	CS	no	USA	June 2005 – September 2009	ETSS	yes	yes
Cappabianca et al.7	2002	CS	no	Italy	January 1997 – July 2001	ETSS	yes	no
Charalampaki et al.8	2009	CS	no	Germany	January 2004 – June 2007	ETSS	yes	NA
Chi F et al.9	2013	Cohort study	no	China	November 2011–October 20112	ETSS	Yes	Yes
Choe et al.10	2008	CS	no	Korea	2004–2007	ETSS	yes	no
Choe et al.10	2008	CS	no	Korea	1997–2004	MTSS	yes	no
Chone et al.11	2014	CS	no	Brazil	January of 2009 – December of 2012	ETSS	yes	NA
Conrad et al.15	2016	Cohort study	no	USA	October 2008 – November 2009	ETSS	yes	NS
Constantino et al.16	2016	CS	no	Brazil	March 2010 – March 2014	ETSS	yes	NS
Cusimano et al.18	2012	Cohort study	No	Canada	October 1994–July 2009	ETSS	Yes	No
Dallapiazza et al.19	2014	Cohort study	no	USA	June 2010 to January 2013	ETSS	yes	yes
Dallapiazza et al.19	2014	Cohort study	no	USA	June 2010 to January 2013	MTSS	yes	yes
Dallapiazza et al.20	2015	CS	no	USA	September 2004 – August 2008	ETSS	yes	NS
Dehdashti et al.23	2008	CS	No	Canada	July 2004 – March 2007	ETSS	yes	no
De Paiva Neto et al.21	2010	Cohort study	No	USA	July 1998–May 2008	ETSS	Yes	Yes
De Witte et al.22	2011	CS	no	Belgium	Februray 2007– December 2010	ETSS	yes	yes
Duz et al.27	2008	CS	no	Turkey	2006–2007	ETSS	yes	NA
Duz et al.27	2008	CS	no	Turkey	1996–2004	MTSS	yes	NA
Fathalla et al.30	2015	Cohort study	no	Canada	2000–2013	ETSS	yes	no
Fathalla et al.30	2015	Cohort study	no	Canada		MTSS	yes	no
Fomekong et al.31	2014	CS	no	Belgium	March 2006 – October 2011	MTSS	yes	NS
Frank et al.32	2006	CS	no	Italy	May 1998 and December 2004	ETSS	yes	NA
Gao et al.33	2016	Cohort study	No	China	January 2012–November 2014	ETSS	Yes	NA
Gao et al.33	2016	Cohort study	No	China	January 2012–November 2014	MTSS	Yes	NA
Gondim et al.35	2011	CS	no	Brazil	January 1998–december 2009	ETSS	yes	yes
Guo Dong et al.37	2016	Cohort study	No	China	June 2010–July 2014	ETSS	Yes	NA
Guo Dong et al.37	2016	Cohort study	No	China	June 2010–July 2014	MTSS	Yes	NA
Guvenc et al.38	2016	Cohort study	no	Turkey	June 2000 – June 2014	ETSS	yes	no
Guvenc et al.38	2016	Cohort study	no	Turkey	June 2000 – June 2014	ETSS	yes	no
Han S et al.39	2013	Cohort study	No	China	May 2009–June 2012	ETSS	Yes	Yes
Hofstetter et al.42	2011	CS	yes	USA	February 2004–january 2010	ETSS	yes	no
Jain et al.44	2007	RT	yes	India	NA	ETSS	yes	no
Jain et al.44	2007	RT	yes	India	NA	MTSS	yes	no
Jang JH et al.45	2016	Cohort study	No	S. Korea	April 1998–December 2014	ETSS	Yes	Yes
Jho, et al.47	2001	CS	no	USA	1993–1999	ETSS	yes	NA
Juraschka et al.48	2014	CS	no	Canada	January 2006 – June 6	ETSS	yes	no
Karppinen et al.50	2015	Cohort study	no	Finland	2000 – 2011	ETSS	yes	no
Karppinen et al.50	2015	Cohort study	no	Finland	2000 – 2011	MTSS	yes	no
Kenan et al.51	2006	Cohort studt	No	Turkey	September 1997–June 2005	ETSS	Yes	No
Kumar et al.53	2012	CS	no	Singapore	June 1990–May2008	ETSS	yes	yes
Kuo et al.54	2016	CS	no	Taiwan	2000 – 2009	ETSS	yes	yes
Kurosaki et al.55	2000	Cohort study	No	Germany	January 1991–November 1999	MTSS	Yes	NA
Lampropoulos et al.56	2013	CS	yes	Greece	2004–2011	MTSS	yes	yes
Liu et al.60	2015	CS	no	China	January 2009 – December 2012	MTSS	yes	no
Messerer et al.64	2011	Cohort Study	No	France	2006–2009	ETSS	yes	yes
Messerer et al.64	2011	Cohort Study	No	France	2006–2009	MTSS	yes	yes
Mortini P et al.67	2005	CS	No	Italy	1990–2002	MTSS	NA	No
Nakao et al.68	2010	Cohort study	No	Japan	2000–2008	ETSS	Yes	NA
Nie al.69	2015	CS	NA	China	January 2012 – December 2012	ETSS	yes	NA
O’Malley et al.70	2008	Cohort study	no	USA	2003–2008	ETSS	yes	yes
O’Malley et al.70	2008	Cohort study	no	USA	2003–2008	MTSS	yes	yes
Ogawa et al.71	2015	CS	no	Japan	October 2008 – January 2014	MTSS	yes	yes
Pinar et al.74	2015	Cohort study	No	Turkey	February 2011–December 2013	ETSS	Yes	NA
Qureshi et al.75	2016	CS	no	USA	2006 – 2012	ETSS	yes	yes
Sheehan et al.78	1999	CS	no	USA	1995–1997	ETSS	yes	NA
Sheehan et al.78	1999	CS	no	USA	1995–1997	MTSS	yes	NA
Song et al.80	2014	CS	no	China	January 2007 – January 2012	ETSS	yes	NA
Thomas et al.82	2014	CS	yes	USA	NA	ETSS	yes	NA
Tosaka et al.83	2015	CS	no	Japan	October 2003 – October 2009	ETSS	yes	yes
Wang et al.84	2015	CS	no	China	January 2007 – June 2013	ETSS	yes	yes
Wongsirisuwan et al.86	2014	CS	no	Thailand	January 2003 – September 2013	ETSS	yes	yes
Yan et al.87	2015	CS	no	China	January 2013 – June 2013	MTSS	yes	NA
Yildirim et al.88	2016	CS	no	Turkey	August 2009 – May 2014	ETSS	yes	no
Zaidi et al.89	2016	Cohort study	no	USA	October 2011–June 2014	ETSS	yes	yes
Zaidi et al.89	2016	Cohort study	no	USA	October 2011–June 2014	MTSS	yes	yes
Zhan et al.90	2015	CS	no	China	January 2008 – December 2014	ETSS	yes	NA
Zhang, X et al.91	2008	CS	no	China	1998 – 2005	ETSS	yes	NA
Zhou et al.92	2014	CS	no	China	January 2007– July 2012	ETSS	yes	yes

Abbreviations: CS, Case series; RT, Randomized Trail; ETSS, Endoscopic Transsphenoidal surgery; MTSS, Microscopic Transsphenoidal Surgery; NA, Not Available; iMRI: intraoperative MRI

Table 2.

Patient Characteristics in the Selected Studies

Study	# PA	AGE	Gender		According to Size		According to Function		Functional Pituitary Adenoma
		(Mean±SD)	M	F	% Microadenoma	% Macroadenoma	% FPA	%NFPA	% GH	% ACTH	%PRL
Bodhinayake et al.4	64	46.7 (16.7)	24 (37.5%)	40 (62.5%)	14.10%	78.1%	NA	NA	NA	NA	NA
Bokhari et al.5	79	56.7 ± 16.3	35 (44%)	44 (56%)	8.86%	91.14%	50.63%	49.37%	47.50%	10.00%	40.00%
Campbell et al.6	27	45.7	14 (53.8%)	12 (46.2%)	14.81%	81.48%	100.00%	0.00%	85.19%	NA	11.11%
Cappabianca et al.7	146	46.06	68 (46.57%)	78 (53.4%)	14.38%	85.62%	45.21%	54.79%	54.55%	19.70%	19.70%
Charalampaki et al.8	134	57	70 (52.23%)	80 (59.7%)	11.19%	44.78%	44.03%	55.97%	44.07%	27.12%	27.12%
Chi et al.9	80	50.84 (13.62)	45 (56%)	35 (44%)	20%	80%	57%	43%	19.6%	6.5%	56.5%
Choe et al.10	12	47 ± 12	5 (41.6%)	7 (58.33%)	25.00%	75%	100.00%	0.00%	75.00%	25.00%	0.00%
Choe et al.10	11	48 ± 10	2 (18.1%)	9 (81.8%)	27.27%	72.73%	100.00%	0.00%	72.73%	27.27%	0.00%
Chone et al.11	47	54	NA	NA	NA	NA	36.17%	63.83%	41.18%	29.41%	29.41%
Conrad et al.15	40	56.5 (−)	20 (50%)	20 (50%)	10%	90%	27.50%	72.50%	NA	NA	2
Constantino et al.16	28	46 (−)	17 (60%)	11 (40%)	0	100%	82%	7.10%	NA	0	1
Cusimano et al.18	29	50.3 (15.4)	16 (55%)	13 (45%)	0	100%	13.8%	86.2%	75%	0	25%
Dallapiazza et al.19	56	56.2± 12.8	27 (48.21%)	29 (51.78%)	NA	NA	0%	100%	0	0	0
Dallapiazza et al.19	43	56.7± 16.9	24 (55.8%)	19 (44.1%)	NA	NA	0%	100%	0	0	0
Dallapiazza et al.20	80	56.6 (13)	38 (47.5%)	42 (52.5%)	0	100%	0%	100%	0	0	0
Dehdashti et al.23	200	49.9 (NA)	109 (54.5%)	91 (45.5%)	79%	21%	44.5%	55.5%	38.2%	30.3%	28.1%
De Paiva Neto et al.21	51	48 (16)	63%	37%	0	100%	23.6%	76.4%	25%	8.3%	66.7%
De Witte et al.22	81	50.07± 13.81	44 (53%)	39 (47%)	12.35%	90.12%	NA	49.38%	NA	NA	NA
Duz et al.27	28	NA	NA	NA	NA	NA	46.43%	42.86%	61.54%	23.08%	15.38%
Duz et al.27	40	NA	NA	NA	NA	NA	45.00%	52.50%	55.56%	22.22%	22.22%
Fathalla et al.30	42	43.2	21 (50)	21 (50)	16.7%	83.3%	100%	0%	0	0	0
Fathalla et al.30	23	42.1	7 (30)	16 (70)	26.1%	73.9%	100%	0%	0	0	0
Fomekong et al.31	73	50 (17)	46 (63)	27 (37)	0	100%	NA	NA	NA	NA	NA
Frank et al.32	173	NA	191 (45.5%)	227 (54.5%)	NA	NA	128.90%	1.12	39.91%	26.01%	32.74%
Gao et al.33	60	44.6	26 (43.3%)	34 (56.6%)	21.6%	78.3%	55%	45%	21.2%	15.1%	63.6%
Gao et al.33	45	48.8	19 (42.2%)	26 (57.7%)	22.2%	77.7%	51.1%	48.8%	17.4%	13%	69.5%
Gondim et al.35	301	42.44± 15.31	134 (44.5%)	167 (55.5%)	17.61%	82.39%	55.15%	44.85%	40.96%	22.29%	28.92%
Guo-Dong et al.37	100	43.4 (14)	59%	41%	NA	NA	48%	52%	18.75%	8.3%	68.75%
Guo-Dong et al.37	147	40.4 (14.2)	53 (36%)	94 (64%)	NA	NA	53.1%	46.9%	12.8%	8.9%	73.1%
Guvenc et al.38	45	48.3 (14.1)	19 (42.2)	26 (57.8)	31.10%	68.90%	51.10%	48.90%	24.40%	8.90%	11.10%
Guvenc et al.38	49	37.0 (13.0)	18 (36.7)	31 (63.3)	14.30%	85.70%	71.40%	28.60%	36.70%	2%	26.50%
Han et al.39	250	43.8	99 (39.6%)	151 (60.4%)	17.2%	82.8%	41.2%	58.8%	40.8%	19.4%	32%
Hofstetter et al.42	86	45.2±1.8	37 (43.0%)	49 (57.0%)	NA	NA	100.00%	NA	38.37%	20.93%	40.70%
Jain et al.44	10	40.1	NA	NA	10.00%	NA	NA	NA	NA	NA	NA
Jain et al.44	10	31.6	NA	NA	20.00%	NA	NA	NA	NA	NA	NA
Jang JH et al.45	331	48.4	145 (43.8%)	186 (56.2%)	29.6%	70.4%	52.6%	47.4%	11.5%	16.7%	59.8%
Jho, et al.47	128	NA	70 (54.68)	90 (70.3)	23.44%	76.56%	NA	53.13%	NA	NA	NA
Juraschka et al.48	73	54.48 (14.8)	50 (68.5)	23 (31.5)	0	100%	11%	89%	NA	NA	NA
Karppinen et al.50	41	58.5 (16)	23 (56)	18 (44)	0	100%	0	100%	0	0	0
Karppinen et al.50	144	58.4 (13)	95 (66)	49 (34)	NA	NA	0	100%	0	0	0
Kenan et al.51	59	44.7	NA	NA	14%	86%	75.8%	24.2%	35.6%	6.8%	47.4%
Kumar et al.53	164	53.1	80 (48.7)	91 (55.4)	19.51%	70.73%	NA	38.41%	NA	NA	NA
Kurosaki et al.55.	32	73.9	17 (53%)	15 (47%)	NA	NA	0	100%	0	0	0
Kuo et al.54	38	50.8 (13.1)	24 (63.2)	14 (36.8)	NA	NA	NA	NA	NA	NA	NA
Lampropoulos et al.56	184	49.77±14.23	99(53.8)	NA	NA	NA	47.28%	52.72%	58.62%	26.44%	12.64%
Liu et al.60	1104	NS	407 (36.9)	697 (63.1)	11.30%	88.70%	60.20%	39.80%
Messerer et al.64	82	57	47(57.3)	35 (42.6)	NA	NA	NA	NA	NA	NA	NA
Messerer et al.64	82	56.5	51 (62.19)	31 (37.8)	NA	NA	NA	NA	NA	NA	NA
Mortini P et al.67	361	51.9 ±0.7	NA	NA	NA	NA	NA	100%	0	0	0
Nakao et al.68	43	55	23 (53.4%)	20 (46.6%)	0	100%	0	100%	0	0	0
Nie al.69	52	46.8	24 (46.2)	28 (53.8)	13.50%	86.50%	67.30%	32.70%		0
O’Malley et al.70	21	47.9	15 (60%)	10(40%)	12%	88%	NA	NA	NA	NA	NA
O’Malley et al.70	22	50.8	16 (64%)	9 (36%)	8%	92%	NA	NA	NA	NA	NA
Ogawa et al.71	23	63.5 (13.7)	12 (52.2)	11 (47.8)	NA	NA	95.70%	4.30%	NA	NA	NA
Pinar et al.74	32	48.6	14 (43.8%)	18 (56.2%)	37.5%	62.5%	68.8%	31.2%	36.4%	22.7%	27.3%
Qureshi et al.75	78	52.2 (18.1)	43 (55.1)	35 (44.9)	3.80%	96.20%	NA	NA	NA	NA	NA
Sheehan et al.78	26	59.2 ± 15.1	18 (69.2)	8 (30.7)	0.00%	100%	0.00%	100%	NA	NA	NA
Sheehan et al.78	44	57.8 ± 14.9	31 (70.45)	13 (29.5)	0.00%	100%	0.00%	100%	NA	NA	NA
Song et al.80	22	NA	12 (40.0)	18 (60.0)	NA	NA	100%	0		0
Thomas et al.82	50	NA	21 (42.0)	29 (58.0)	18.00%	82%	24.00%	76.00%		4
Tosaka et al.83	30	51.5	14 (46.7)	16 (53.3)	0	100%	NA	NA	NA	NA	NA
Wang et al.84	1166	40.3 (15.25)	517 (44.3)	649 (55.7)	21.00%	79%	50.50%	49.50%		68
Wongsirisuwan et al.86	38	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
Yan et al.87	99	NA	0 (0.0)	99 (100.0)	68.70%	31.3%	100.00%	0	0	0
Yildirim et al.88	160	48.5	88 (55.0)	72 (45.0)	0	100%	0	100%	0	0	0
Zaidi et al.89	55	55.9 ± 13.8	35 (63.6)	20(36.4)	NA	NA	0.00%	100%	NA	NA	NA
Zaidi et al.89	80	59.1 ± 14.6	50 (62.5)	30 (37.5)	NA	NA	0.00%	100%	NA	NA	NA
Zhan et al.90	313	60.1	188 (60.0)	125 (39.9)	16.90%	83.10%	0	100%	0	0	0
Zhang, X et al.91	78	45.1	36 (46.2%)	42 (53.8%)	14.10%	85.90%	44.87%	55.13%	25.71%	11.43%	48.57%
Zhou et al.92	133	38.3	96 (72.2)	37 (27.8)	12.80%	87.20%	100%	0	0	0	0

Abbreviations: PA, pituitary adenoma; NA, not available; FPA, functional pituitary adenoma; NFPA, nonfunctional pituitary adenoma; GH, growth hormone; PRL, prolactin

Pituitary Adenomas

GTR was available for n=8257 patients (Table 3). Using the fixed-effect model, the pooled rate of GTR among all studies was 71.0% (95%CI: 69.9–72.1%, I²=91.2%; P-heterogeneity<0.01 under the fixed-effect model (Table 4) [4–11, 15, 16, 18–23, 27, 30–33, 35, 37–39, 42, 44, 45, 47, 48, 50–56, 59, 64, 68, 70, 71, 74, 75, 78, 80, 82–84, 86–92]. When eTSS and mTSS were compared, GTR rate was significantly higher in eTSS (n=50 studies, GTR=74.0%, 95%CI: 72.6–75.3%, I²=92.1%; P-heterogeneity<0.01) than in mTSS (n=20 studies, GTR=66.4%, 95%CI: 64.5–68.2%, I²=84.0%; P-heterogeneity<0.01) (Figure 2). This difference was significant in a fixed-effect model (P-interaction<0.01), but not in a random-effect models (P-interaction=0.40). To further assess the considerable heterogeneity in GTR observed in the pituitary adenomas overall, functioning pituitary adenomas (FPA) and non-functioning pituitary adenomas (NFPA) were assessed separately.

Table 3.

Result of Gross Tumor Resection In Pituitary adenoma

Study (Year of Publication)	Surgical Intervention	PA (n)	Total Cases of GTR (n,(%))
			PA	Macroadenoma	Microadenoma	NFPA	FPA	GH	ACTH	PRL
Bodhinayake et al.4	ETSS	64	44/64 (68.7)	NR	NR	NR	NR	NR	NR	NR
Bokhari et al.5	ETSS	79	50/79 (63.2)	43/72 (59.7)	7/7 (100)	19/39 (48.7)	31/40 (77.5)	14/19 (73.68)	4/4 (100)	12/16 (75)
Campbell et al.6	ETSS	26	19/26 (73.1)	NR	NR	NR	19/26 (73.1)	19/26 (73.1)
Cappabianca et al.7	ETSS	146	91/146 (62.3)	73/125 (58.4)	18/25 (85.7)	45/80 (56.2)	46/66 (69.7)	23/36 (63.88)	10/13 (76.9)	10/13 (76.9)
Charalampaki et al.8	ETSS	134	126/134 (94.0)	NR	NR	74/75 (98.7)	52/59 (88.1)	23/26 (88.4)	14/16 (87.5)	15/16 (93.75)
Chi et al.9	ETSS	80	51/80 (63.75)	NR	NR	NR	NR	NR	NR	NR
Choe et al.10	ETSS	12	10/12 (83.3)	NR	NR	NR	10/12 (83.3)	8/9 (88.8)	2/3 (66.6)	NR
Choe et al.10	MTSS	11	8/11 (72.7)	NR	NR	NR	8/11 (72.7)	5/8 (62.5)	3/3 (100)	NR
Chone et al.11	ETSS	47	45/47 (95.7)	NR	NR	28/30 (93.3)	NR	NR	NR	NR
Conrad et al.15	ETSS	40	34/40 (85)	NR	NR	NR	NR	NR	NR	NR
Constantino et al.16	ETSS	28	4/28 (14.3)	4/28 (14.3)	NR	NR	NR	NR	NR	NR
Cusimano et al.18	ETSS	29	23/29 (79.3)	NR	NR	NR	NR	NR	NR	NR
Dallapiazza et al.19	ETSS	56	54/56 (96.4)	NR	NR	54/56 (96.4)	NR	NR	NR	NR
Dallapiazza et al.19	MTSS	43	40/43 (93.02)	NR	NR	40 (93.02)	NR	NR	NR	NR
Dallapiazza et al.20	ETSS	80	57/80 (71)	57/80 (71)	NR	57/80 (71)	NR	NR	NR	NR
Dehdashti et al.23	ETSS	200	176/200 (88)	158/200 (79)	42/200 (21)	98/111 (88)	75/86 (87.2)	29/34 (85)	23/27 (85)	23/25 (92)
De Paiva Neto et al.21	ETSS	51	21/51 (41.2)	NR	NR	NR	NR	NR	NR	NR
De Witte et al.22	ETSS	81	24/81 (29.6)	NR	NR	NR	NR	NR	NR	NR
Duz et al.27	ETSS	28	15/28 (53.5)	NR	NR	NR	NR	NR	NR	NR
Duz et al.27	MTSS	40	20/40 (50)	NR	NR	NR	NR	NR	NR	NR
Fathalla et al.30	ETSS	41	25/41 (61)	NR	NR	NR	25/41 (61)	25/41 (61)	NR	NR
Fathalla et al.30	MTSS	19	8/19 (42)	NR	NR	NR	8/19 (42)	8/19 (42)	NR	NR
Fomekong et al.31	MTSS	73	47/73 (65)	47/73 (65)	NR	NR	NR	NR	NR	NR
Frank et al.32	ETSS	173	106/173 (62.2)	105/172 (61.1)	1/1 (100)	106/173 (62.2)	NR	NR	NR	NR
Gao et al.33	ETSS	60	49/60 (81.7)	37/47 (78.7)	12/13 (92.3)	NR	NR	NR	NR	NR
Gao et al.33	MTSS	45	28/45 (62.2)	19/35 (54.3)	9/10 (90)	NR	NR	NR	NR	NR
Gondim et al.35	ETSS	301	233/301 (77.4)	NR	NR	96/135 (71.1)	137/166 (82.5)	58/68 (85.3)	27/37 (72.9)	41/48 (85.4)
Guo-Dong et al.37	ETSS	100	60/100 (60)	NR	NR	NR	NR	NR	NR	NR
Guo-Dong et al.37	MTSS	147	85/147 (57.8)	NR	NR	NR	NR	NR	NR	NR
Guvenc et al.38	ETSS	45	31/45 (68.9)	20/31 (65)	11/14 (78.6)	NR	NR	NR	NR	NR
Guvenc et al.38	MTSS	49	38/49 (77.6)	32/42 (76.2)	6/7 (85.7)	NR	NR	NR	NR	NR
Han S et al.39	ETSS	250	216/250 (86.4)	NR	NR	NR	NR	NR	NR	NR
Hofstetter et al.42	ETSS	86	65/86 (78.6)	NR	NR	NR	65/86 (75.5)	26/33 (78.8)	13/18 (72.2)	26/35 (74.3)
Jain et al.44	ETSS	10	5/10 (50)	NR	NR	NR	NR	NR	NR	NR
Jain et al.44	MTSS	10	5/10 (50)	NR	NR	NR	NR	NR	NR	NR
Jang JH et al.45	ETSS	331	229/331 (69.2)	NR	NR	98/157 (62.4)		18/20 (90)	25/29 (86.2)	73/104 (68.3)
Jho, et al.47	ETSS	68	53/68 (77.9)	NR	NR	53/68 (77.9)	NR	NR	NR	NR
Juraschka et al.48	ETSS	73	16/73 (24.2)	16/73 (24.2)	NR	NR	NR	NR	NR	NR
Karppinen et al.50	ETSS	41	23/41 (56)	23/41 (56)	NR	NR	NR	NR	NR	NR
Karppinen et al.50	MTSS	144	64/144 (45)	NR	NR	NR	NR	NR	NR	NR
Kenan et al.51	ETSS	59	38/59 (64.4)	38/59 (64.4)	NR	NR	NR	NR	NR	NR
Kumar et al.53	ETSS	66	56/66 (84.8)	NR	NR	56/66 (84.8)	NR	NR	NR	NR
Kurosaki et al.55	MTSS	32	24/32 (75)	NR	NR	NR	NR	NR	NR	NR
Kuo et al.54	ETSS	38	8/38 (21.1)	NR	NR	NR	NR	NR	NR	NR
Lampropoulos et al.56	MTSS	184	124/184 (67.4)	NR	NR	61/97 (62.9)	63/87 (72.4)	36/51 (70.6)	17/23 (73.9)	8/11 (72.7)
Liu et al.59	MTSS	1104	781/1104 (70.7)	NR	NR	NR	NR	NR	NR	NR
Messerer et al.64	ETSS	82	61/82 (74)	NR	NR	61/82 (74)	NR	NR	NR	NR
Messerer et al.64	MTSS	82	41/82 (50)	NR	NR	41/82 (50)	NR	NR	NR	NR
Mortini P et al.67	MTSS	361	234 (64.8)	NR	NR	234 (64.8)	NR	NR	NR	NR
Nakao et al.68	ETSS	43	20/43 (47)	NR	NR	NR	NR	NR	NR	NR
Nie al.69	ETSS	52	46/52 (88.5)	NR	NR	NR	NR	NR	NR	NR
O’Malley et al.70	ETSS	21	14/21 (66.6)	NR	NR	NR	NR	NR	NR	NR
O’Malley et al.70	MTSS	22	17/22 (77.2)	NR	NR	NR	NR	NR	NR	NR
Ogawa et al.71	MTSS	23	20/23 (87.0)	NR	NR	NR	NR	NR	NR	NR
Pinar et al.74	ETSS	32	18/32 (56.2)	9/20 (45)	9/12 (75)	NR	NR	NR	NR	NR
Qureshi et al.75	ETSS	78	73/78 (93.6)	NR	NR	NR	NR	NR	NR	NR
Sheehan et al.78	ETSS	16	7/16 (43.8)	NR	NR	7/16 (43.8)	NR	NR	NR	NR
Sheehan et al.78	MTSS	36	15/36 (41.7)	NR	NR	15/36 (41.7)	NR	NR	NR	NR
Song et al.80	ETSS	22	16/22 (72.7)	NR	NR	NR	16/22 (72.7)	NR	NR	NR
Thomas et al.82	ETSS	50	37/50 (74.0)	NR	NR	NR	NR	NR	NR	NR
Tosaka et al.83	ETSS	30	15/30 (50.0)	15/30 (50.0)	NR	NR	NR	NR	NR	NR
Wang et al.84	ETSS	1166	1069/1166 (91.7)	829/921 (90.0)	240/245 (98.0)	NR	NR	NR	NR	NR
Wongsirisuwan et al.86	ETSS	38	28/38 (73.3)	NR	NR	NR	NR	NR	NR	NR
Yan et al.87	MTSS	99	88/99 (88.9)	NR	NR	NR	88/99 (88.9)	NR	NR	88/99 (88.9)
Yildirim et al.88	ETSS	160	144/160 (90.0%)	144/160 (90.0%)	NR	144/160 (90.0)	NR	NR	NR	NR
Zaidi et al.89	ETSS	55	43/55 (78.2)	NR	NR	43/55 (78.2)	NR	NR	NR	NR
Zaidi et al.89	MTSS	80	65/80 (81.3)	NR	NR	65/80 (81.3)	NR	NR	NR	NR
Zhan et al.90	ETSS	313	239/313 (76.4)	NR	NR	239/313 (76.4)	NR	NR	NR	NR
Zhang X et al.91	ETSS	78	62/78 (79.4)	NR	NR	NR	NR	NR	NR	NR
Zhou et al.92	ETSS	133	110/133 (82.7)	NR	NR	NR	110/133 (82.7)	110/133 (82.7)	NR	NR

Abbreviations: GTR, gross total resection, PA, pituitary adenoma; NR, not reported; FPA, functional pituitary adenoma; NFPA, nonfunctional pituitary adenoma; GH, growth hormone; PRL, prolactin

Table 4.

Results of Gross tumor resection rate and 95% Confidence Interval in the Following case (Combine Subgroups Using Fixed- and random-effect model)

Operative modality	Number Of studies	Fixed-effect model		Random-effect model		Heterogeneity		P-interaction		P-value for Begg’s test
		GTR rate (%)	95%-CI	GTR rate (%)	95%-CI	I2 value (%)	P-heterogeneity	Fixed effect model	Random effect model
ETSS PA Overall	50	74.0	72.6–75.3	71.2	66.2–75.8	92.1	<0.01	<0.01	0.44	0.33
MTSS PA Overall	19	66.6	64.6–68.6	67.5	58.5–75.4	84.8	<0.01
ETSS FPA	13	75.8	72.8–78.5	76.7	70.5–81.8	63.9	<0.01	0.92	0.67	0.91
MTSS FPA	5	75.5	69.1–80.9	74.1	62.2–83.2	79.0	<0.01
ETSS NFPA	19	71.0	68.7–73.3	74.1	67.5–79.7	86.3	<0.01	<0.01	0.127	0.08
MTSS NFPA	8	60.7	57.3–64.0	64.6	53.1–74.7	87.4	<0.01

Abbreviations: GTR, gross total resection, PA, pituitary adenoma; NR, not reported; FPA, functional pituitary adenoma; NFPA, nonfunctional pituitary adenoma; ETSS, Endoscopic Transsphenoidal surgery; MTSS, Microscopic Transsphenoidal Surgery

Figure 2.

Subgroup Analysis by The type of TSS, Forest Plot of Gross tumor resection rate and 95 % CI for Patient with PA who had transsphenoidal Surgery

Functioning Pituitary Adenomas

Eighteen studies reported GTR rate among FPAs (n=1170) [5–10, 18, 21, 23, 30, 33, 35, 37, 39, 42, 45, 51, 55, 56, 74, 80, 87, 92]. Using the fixed-effect model, the overall GTR rate was 75.7% (95%CI: 73.1–78.2%, I²=67.5%, p-heterogeneity<0.01). In a subgroup analysis for eTSS vs. mTSS, GTR rate was not significantly different comparing eTSS (GTR=75.8%, 13 studies) and mTSS (GTR=75.5%, 5 studies) using both the fixed- (P-interaction=0.92) and the random-effect models (P-interaction=0.67, Figure 3).

Figure 3.

Subgroup Analysis by The type of TSS, Forest Plot of Gross tumor resection rate and 95 % CI for Patient with Functional PA who had Transsphenoidal Surgery

All of the 13 studies reporting GTR after eTSS were published after 2000 and only 3 studies reported GH-producing to be the type of FPA. Using the fixed-effect model, significant sources of heterogeneity were identified for microadenoma percent (P=0.04; high percent: 67.6%, 3 studies, which had a lower GTR than studies with low percent microadenoma: 80.1%, 2 studies), number of centers (P=0.01; single center: 74.9%, multiple centers: 87.2%), age (P=0.01; 36–40 years: 82.7%, 41–45 years: 70.5%, 46–50 years: 71.5%, 56–60 years: 83.2%), and study design (P<0.01; cohort: 66.7%; case series: 78.3%). Non-significant interactions were identified for continent, country, male percent, and number of surgeons (all P>0.05). No significant sources of heterogeneity were identified using the random-effect model (not shown). Meta-regression on journal impact factor and year of publication were not significant in both random- and fixed-effect models (P >0.05 for all).

All of the five studies reporting GTR after mTSS were case series, conducted in a single center and published after 2000. Using the fixed-effect model, significant interactions were identified for age category (p=0.03; category 51–55: 77.3%, 1 study, which had a higher GTR than each of 46–50: 72.4%, 2 studies; 41–45: 42.1%, 1 study), type of FPA (p<0.01; 1 study with prolactinoma patients had a higher GTR rate of 88.9% than one study with GH-producing: 42.1%), in addition to continent (p<0.01; GTR in Asia: 86.7%, 2 studies, which was higher than in Europe: 72.4%, 1 study; and North America: 59.5%, 2 studies). Using the random-effect model, however, sources of heterogeneity could be identified for age category: p<0.01; and types of FPA: P<0.01. Other variables such as continent, male percent, single surgeon, and microadenoma percentage were not a significant source of heterogeneity. Meta-regression on journal impact factor was significant in a fixed-effect model (slope=−0.74: 95%-CI: −1.47; −0.01, P=0.046) which suggested that a lower GTR percent was associated with a higher journal impact factor, but this association was not significant in a random-effect model (P=0.38). Meta-regression on year of publication was not significant in both models (P>0.05 for both).

Non-Functioning Pituitary Adenomas

Twenty-seven studies reported GTR for NFPA (n=2,655) [5, 7, 8, 11, 19, 20, 23, 32, 35, 45, 53, 56, 64, 78, 88–90]. Under the fixed-effect model, the overall GTR rate for NFPA was 67.3% (95%CI: 65.3–69.2%, I²=87.7%, p-heterogeneity<0.01). In a subgroup analysis for eTSS vs. mTSS, GTR rate was significantly higher in eTSS (GTR=71.0%, 19 studies) than in mTSS (GTR=60.7%, 8 studies) (P-interaction<0.01), although this difference was not significant in the random-effect model (P-interaction= 0.13, Figure 4).

Figure 4.

Subgroup Analysis by The type of TSS, Forest Plot of Gross tumor resection rate and 95 % CI for Patient with Non-Functional PA who had Transsphenoidal Surgery

Among the 19 studies reporting GTR after eTSS, they were all conducted in a single center. Using the fixed-effect model, significant interactions were identified for the following variables: continent: P <0.01 (GTR in North America: 78.2%, 6 studies, which was higher than in Europe: 68.4%, 6 studies; Asia: 70.5%, 4 studies; South America: 73.3%, 2 studies; and Australia: 48.7%, 1 study); age category: P <0.01 (age category 46–50: 74.5%, 2 studies, which had a higher GTR than each of 51–55: 46.5%, 1 study, and 56–60: 73.7%, 7 studies); publication after 2000 (P=0.02; before 2000: 43.8%, 1 study, vs. after 2000 71.3%, 18 studies); study design (P<0.01; cohort: 58.5%, 3 studies; case series: 73.6%; 16 studies). Non-significant interaction was identified for microadenoma percent (P=0.41) and male percentage (P=0.66). Using the random-effect model, only study design was identified as a significant source of heterogeneity (P<0.01). Other variables such as number of surgeons were not available in many studies and were therefore not used for stratification. Meta-regression on year of publication was significant in a fixed-effect model (P<0.01, beta: 0.03) suggesting an increased GTR with later publication year, but not in a random-effect model (P=0.15). Meta-regression on journal impact factor was not significant in a random-effect model (P=0.20), yet it was significant in the fixed-effect models (beta: −0.13; P<0.01) suggesting that studies published in a higher impact factor journal tended to report a lower GTR than studies published in lower impact factor journals.

Among the eight single center studies reporting GTR after mTSS, significant interactions were identified with the following variables using the fixed-effect model: continent (P<0.01; GTR in North America 71.8%, 3 studies; GTR in Europe 59.0%, 5 studies), age (P=0.013; age category 71–75: 75%, 1 study, which had a higher GTR than 56–50: 54.4%, 5 studies), study design: (P<0.01; cohort: GTR=49.2%, 2 studies; case series: GTR=63.5%, 6 studies), and publication before 2000 (P=0.019; before 2000: 41.7%, 1 study, after 2000: 61.6%, 7 studies). However, using the random-effect model, no significant sources of heterogeneity could be identified for the following variables: continent (P-interaction=0.15), age category (P=0.96), publication before 2000 (P=0.141), and study design (P=0.524). While 7 studies did not report the microadenoma percentage, only 1 study indicated it had a higher macroadenoma percentage; 6 other studies reported a higher male percentage. Meta-regression on journal impact factor was significant with the fixed-effect model (slope=0.13, 95% CI: 0.008–0.25, p=0.04) indicating a direct association between a higher journal impact factor and a higher GTR rate, but this association was not significant in a random-effect model (p=0.79). Meta-regression on study year was not significant in random- (P=0.42) or fixed-effect (P=0.41) models.

Publication Bias

A symmetrical inverted funnel plot suggested the absence of publication bias in the GTR analysis for pituitary adenomas (Appendix 4). Furthermore, no significant publication bias was identified using Begg’s (P=0.29) and Egger’s test (P=0.52). In the analysis for FPA, a symmetrical funnel plot suggested the absence of publication bias (Appendix 5), which was also confirmed by Begg’ (P=0.91) and Egger’s Tests (P=0.82). In the analysis for NFPA, a slightly asymmetrical inverted funnel plot suggested the presence of publication bias where smaller studies showing a lower GTR rate could have been unpublished (Appendix 6); however, Begg’s (P=0.11) and Egger’s test (P=0.07) indicated no publication bias. After imputing 4 studies to the left of the pooled estimate using the trim and fill method, the new pooled GTR rate slightly decreased from 67.3% to 66.5% under the fixed effect model.

Discussion

This meta-analysis indicates that among patients who are not randomly allocated to either approach, eTSS results in a higher rate of GTR compared to mTSS, for all pituitary adenomas and for NFPA in fixed-effect models. For all FPAs, however, eTSS does not offer a significantly higher rate of GTR in both models. Despite these significant associations, the great heterogeneity among studies reporting both approaches could not be corrected by meta-regression, indicating that the results should be interpreted with caution.

Despite detailed meta-regression by both study and patient-level characteristics, the heterogeneity between studies of both modalities could not be alleviated. Due to the relatively low quality of evidence of the included studies, which mostly consisted of retrospective case series, this heterogeneity is not surprising. Some of the reasons for the great heterogeneity may include the learning curve associated with endoscopic resection, with more and less experienced surgeons reporting significantly different rate of GTR.

One recent survey among neurosurgeons found a significant correlation between the number of pituitary adenomas resections performed and post-operative complication rates (p<0.05) [12]. For GTR specifically, one study found a significant relation when comparing the first 40 patients with the last 40 patients in their case series (52.5% vs. 75.0%, p=0.036), while another study only found a nonsignificant trend towards higher rate of GTR with growing experience [5, 9]. However, another study comparing an inexperienced neurosurgeon performing eTSS to an experienced neurosurgeon performing mTSS showed no significant difference in GTR (p=0.67), suggesting learning curve may not always compromise GTR [89]. In a multivariate model, however, the same study showed that larger pituitary adenomas were associated with a lower extent of resection [89]. In this meta-analysis, only a difference in percentage of macroadenomas was identified as a source of heterogeneity for mTSS NFPA resection, and difference in microadenoma percentage as a source of heterogeneity for eTSS FPA resection. The lack of a significant difference in GTR for eTSS and mTSS may be explained by longer experience with microscopic resection mTSS, despite improved visibility with eTSS.

One other meta-analysis also reported a significant difference in GTR between eTSS and mTSS, but heterogeneity was not described (79% vs. 65% respectively, p<0.01) [24]. Similarly, one study examining 15 cohort studies also reported a higher rate of GTR for eTSS (OR = 1.86, 95%-CI: 1.36–2.54) [34]. Another study found similar results for pituitary adenomas invading the cavernous sinus (47% vs. 21% respectively, p<0.01) [26]. Three other systematic reviews have suggested no significant differences in GTR between the two modalities [76, 79, 81].

Although it remains unclear which of the two treatment modalities, eTSS or mTSS, is superior for GTR, other factors may also play a key role in outcomes for patients with pituitary adenomas, and this meta-analysis cannot fully address these concerns. For example, eTSS may be associated with shorter length of stay and lower costs [24, 36, 73, 76]. Other experts have suggested, however, that eTSS, which generally requires longer operative times, may adversely affect both patient and financial outcomes [66]. Furthermore, one meta-analysis found an association between eTSS and vascular complications when compared to mTSS (1.58% vs. 0.50%, p<0.01) [1]. Proposed reasons for this difference include more aggressive surgical excision in patients undergoing eTSS, perhaps due to the superior visualization permitted by this modality. Other patient-related factors that may alter the choice may be quality of life and visual improvement after surgery, which have not been compared between the modalities [62, 85]. Also, a meta-analysis showed that eTSS was associated with more post-operative visual improvement [24]. Remission of hypersecretion of FPA may also form an indication for either of the modalities, although one meta-analysis showed a non-significant difference [36, 67]. This is particularly relevant as for most FPAs the main goal of the surgery is to achieve hormonal recovery instead of GTR [29, 67]. This is why hormonal recovery could be viewed as a far superior outcome to GTR for FPA patients. Nevertheless, GTR is suggested to be predictive of hormonal recovery [42]. However, it remains to be elucidated what the exact contribution of GTR is to post-operative hormonal recovery rate, as many other factors also contribute to this outcome (e.g., dopamine-antagonists for prolactinoma) [72]. Finally, recurrence, progression free and overall survival, which were also not directly compared, could further aid decision making. Recently, an analysis of nearly 6000 operations demonstrated that eTSS was associated with higher rates of complications, longer postoperative hospital stays, and increased costs when compared to mTSS. It is important to remember that these economic factors may also play a role in decisions regarding methodological choice, beyond just patient- and prognosis-related variables [2].

Strengths of this meta-analysis include the systematic search strategy and fully updated reference list. This is the largest meta-analysis conducted to date on this topic, and the second to identify significant difference in GTR between the two modalities [24]. Additionally, this meta-analysis reported and attempted to address heterogeneity via subgroup analysis by numerous study and patient-level characteristics.

Limitations of this meta-analysis include the high heterogeneity identified among the studies for both eTSS and mTSS. Additionally, odds ratios or relative risks could not be calculated due to the study design of the included studies as the vast majority was retrospective case series. Furthermore, due to inconsistent reporting among the studies included, meta-regression by Knosp score, Hardy-Wilson tumor grading, or asymmetric suprasellar extension was not possible [26]. Furthermore, using both fixed- and random-effect models may help determine the true difference in GTR, but a random-effect model is often not significant when a fixed-effect model is. As with any meta-analysis, its strength is determined only by the strength of the studies included within it. The literature on this topic mostly consists of retrospective case series of varying size; thus, pooled analysis is limited in showing causality. Furthermore, it was not possible to incorporate surgeon experience, which may also influence GTR rate [5, 9]. Surgical outcomes after giant pituitary adenomas resection could not be compared separately as only outcomes after ETSS were reported in five studies and after ETSS, MTSS, and craniotomy in one study [16, 18, 21, 48, 54, 68]. The latter suggests that ETSS results in significantly higher GTR rate among giant pituitary adenomas [18]. This study also examined only GTR and not the many other factors that determine selection of surgical modality. GTR is an important but limited marker for surgical success, especially when resecting FPAs, for which hormonal recovery determines surgical success, and when stereotactic radiosurgery (SRS) is available [28, 67]. This limits the implications of this meta-analysis for FPA patients.

As the technology for eTSS continues to advance, it is likely that eTSS will continue to displace mTSS as the primary approach for sellar lesions, regardless of whether carefully collected evidence indicates superiority. The gold standard for comparison between the two modalities would of course be a prospective, randomized, controlled trial comparing eTSS to mTSS for a large number of patients, as suggested by the IDEAL (Idea, Development, Exploration, Assessment, Long-term Follow-up, Improving the Quality of Research in Surgery) Framework [63]. The IDEAL criteria require careful introduction accompanied by prospective evaluation for initial patients. This should than be followed by a randomized controlled trial to show true benefit [63]. There are many reasons why such a study is unlikely to occur, including surgeon preference and difficulties with patient enrollment. In light of these difficulties and the unlikelihood of such high-quality data, meta-analyses of currently existing studies represent the highest quality data available. Further studies may be improved by focusing on smaller subsets of these reports with the aim to reduce heterogeneity and identify more granular differences in the two approaches. Furthermore, a focus on evaluation of relevant outcomes to patients, such as hormonal recovery for FPA, visual recovery, and quality of life, is of vital importance. Also, alternative trial design may aid finding methodologically just ways of comparing these surgical modalities [61, 63].

Conclusion

The pooled GTR rate in all pituitary adenoma patients undergoing eTSS (74.0%) was significantly higher than the GTR rate in patients undergoing mTSS (66.6%). For NFPA, eTSS resulted in a significantly higher GTR rate (71.0%) than mTSS (60.7%) in a fixed-effect model. However, none of these differences were significant in random-effect models. A direct comparison between the two modalities was impossible, however, due to the high heterogeneity among studies.

Appendices

Appendix (1): Search Strategy

Pubmed

(“Pituitary Neoplasms”[Mesh] OR “Pituitary Neoplasms/surgery”[Mesh] OR Pituitary Neoplasms[TW] OR Pituitary Neoplasm[TW] OR Neoplasm, Pituitary[TW] OR Neoplasms, Pituitary[TW] OR Pituitary Tumors[TW] OR Pituitary Tumor [TW] OR Tumor, Pituitary[TW] OR Tumors, Pituitary[TW] OR Adenoma, Pituitary[TW] OR Adenomas, Pituitary[TW] OR Pituitary adenoma [TW] OR Pituitary Adenomas[TW] OR Macroadenoma [TW] OR Microadenoma [TW] OR Pituitary Microadenoma [TW]) And (“Neuroendoscopy”[Mesh] OR “Neuroendoscopes”[mesh] OR Neuroendoscopy [TW] OR Neuroendoscope*[TW] OR “Neuroendoscopy/adverse effects”[Mesh] OR “Neuroendoscopy/methods”[MAJOR] OR “Neuroendoscopes”[MAJOR] OR trans-sphenoidal[tw] OR Transsphenoidal [tw] OR Transnasal endoscopic resection [TW] OR TER [TW] OR Transsphenoidal pituitary surgery[TW] OR Transsphenoidal endoscopic surgery [TW] OR endoscopic transsphenoidal surgery [TW] OR endoscopic endonasal transsphenoidal [TW] OR nasal endoscopic transsphenoidal surgery [TW] OR ETSS [tw] OR trans-nasal [TW] OR Transsphenoidal microscopic surgery [TW] OR microscopic transsphenoidal surgery [TW] OR MTS [TW]OR microscopic endonasal transsphenoidal [TW] OR MTSS [TW] OR micro-surger*[TW] OR microsurger* [TW] OR “Cerebral Revascularization”[Mesh] OR “Microsurgery”[Mesh:NoExp]) AND (“neoplasm, residual”[MeSH] OR residual neoplasm [Text Word] OR residual tumor [tw] OR residual cancer [tw] OR GROSS TUMOR RESECTION [TW] OR “Length of Stay”[Mesh] OR length of stay [tw] OR “perioperative period”[MeSH Terms] OR perioperative period [Text Word] OR “postoperative complications”[MeSH] OR postoperative complication*[Text Word] OR complication rate[tw])

Embase

exp hypophysis tumor/su [Surgery] OR Pituitary Neoplasms.ti,ab,tw. OR Pituitary Tumors.ti,ab,tw.OR Pituitary adenoma.ti,ab,tw. OR exp hypophysis adenoma/OR Pituitary Microadenoma.ti,ab,tw. OR Pituitary Adenomas.ti,ab,tw. OR exp microadenoma/su [Surgery] OR microadenoma.ti,ab,tw. OR exp adenoma/su [Surgery] OR Macroadenoma.ti,ab,tw. AND Exp neuroendoscopy/OR neuroendoscopy.ti,ab,tw. OR Neuroendoscopic surgery.tw OR neuroendoscopic procedure.tw. OR neuroendoscope.tw. OR neuroendoscopes.tw OR neurological Procedure.tw. OR exp transsphenoidal surgery/OR transsphenoidal surgery.ti,ab,tw. OR Transsphenoid surgery.tw. OR transsphenoidal treatment.tw. OR Transsphenoidal microscopic surgery.ti,ab,tw. OR Transsphenoidal endoscopic surgery.ti,ab,tw. OR Microscopic transsphenoidal surgery.ti,ab,tw. OR Endoscopic Transsphenoidal surgery.ti,ab,tw. OR Microscopic endonasal transsphenoidal.ti,ab,tw. OR Endoscopic endonasal transsphenoidal.ti,ab,tw. OR Nasal endoscopic transsphenoidal surgery.ti,ab,tw. OR endoscopic neurosurgery.ti,ab,tw. AND Gross tumor resection.ti,ab,tw OR exp perioperative period/OR Peri-operative period.ti,ab,tw OR Complication Rate.ti,ab,tw OR postoperative complications.ti,ab,tw OR exp Postoperative Complication/OR Length of Stay.ti,ab,tw. OR exp Length of stay.

Cochrane

Cochrane Central Register of Controlled Trials (CCTR) “Pituitary adenoma” (Title, abstract, keywords) And Endoscopic Transsphenoidal surgery (Title, abstract, keywords) OR Microscopic Transsphenoidal surgery (Title, abstract, keywords) “Pituitary adenoma” (Title, abstract, keywords) And Endoscopic Transsphenoidal surgery (Title, abstract, keywords) OR Microscopic Transsphenoidal surgery (Title, abstract, keywords And “outcome” Cochrane database for SR Endoscopic Transsphenoidal surgery (Title, abstract, keywords) OR Microscopic Transsphenoidal surgery (Title, abstract, keywords) AND gross tumor resection (KEYWORS) “Pituitary adenoma” (Title, abstract, keywords) And Endoscopic Transsphenoidal surgery (Title, abstract, keywords) OR Microscopic Transsphenoidal surgery (Title, abstract, keywords “Pituitary adenoma” (Title, abstract, keywords) And Endoscopic Transsphenoidal surgery (Title, abstract, keywords) OR Microscopic Transsphenoidal surgery (Title, abstract, keywords And “outcome” Cochrane Methodology Register Endoscopic Transsphenoidal surgery (Title, abstract, keywords) OR Microscopic Transsphenoidal surgery (Title, abstract, keywords) AND gross tumor resection (keywords) “Pituitary adenoma” (Title, abstract, keywords) And Endoscopic Transsphenoidal surgery (Title, abstract, keywords) OR Microscopic Transsphenoidal surgery (Title, abstract, keywords) And “outcome”

Appendix (2): Studies excluded in the Analysis of Gross Tumor Resection (GTR)

Author	Year of Publica tion	Countr y	Study Design	Retrospe ctive	Prospec tive	# Of Grou ps	Diagnosis	Surgical Interventi on	Reason
Abosch, A	1998	USA	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
Atkinson et al.	2008	USA	Not clear	Yes	No	2	Cushing Disease	STT/CTS	COMPARING MTSS VS COMBINED (IT DIDN’T MEET OUR CRTIERIA)
Bao X	2016	China	CS	Yes	No	1	PA	ETSS	NO AVAILABLE INFORMATION ABOUT GTR
Barzaghi, L.	2007	Italy	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
Berker, M.	2012	Turkey	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION
Berkman S.	2014	Germany	CS	Yes	No	1	PA	MTSS	NO AVAILABLE INFORMATION ABOUT GTR
Black, P. M.	1987	USA	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
Cappabianca, P.	1999	Italy	CS	Yes	No	2	PA	ETSS/MTSS	Overlapping cohorts
Cappabianca, P.	2002	Italy	CS	Yes	No	1	PA, Craiopharyingiomas, chordoma	ETSS	Overlapping cohorts
Casler	2005	USA	CS	Yes	No	2	PA	ETSS/MTSS	IT REPORTED GTR IN ETSS AND MTSS BUT THEY WERE USED TWO OR COMBINED TECHNIQUE FOR 10 PATIENT AND RESULT REOPORTED IN GENERAL (I DON’T KNOW THE RESULT FOR THEM)
Chacko, A. G.	1997	Vellore	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
Chen, L.;	2011	China	CS	No	Yes	1	PA	EATSS	It was EATSS doesn’t meet our criteria
Cheng, R. -X;	2011	China	CS	Yes	No	2	PA	ETSS/MTSS	GTR INFORMATION NA / THEY MENTION REMISSION RATE HERE INFORM OF GTR BUT IT IS DEFINED IN THE STUDY AS HORMONAL CONTROL
Cho D.Y	2002	China	Randomized	NA	NA	2	Prolactinomas	ETSS/MTSS	NO AVAILABLE INFORMATION GTR
Cho, D. Y.;	2002	China	CS	No	No	2	PA	ETSS/MTSS	Didn’t design study to report GTR INFORMATION
Chung T.G.	2015	U.S.A.	CS	Yes	No	NS	PA	NS	NO AVAILABLE INFORMATION ABOUT GTR
Comtois, R.	1991	Canada	CS	Yes	No	1	PA	ETSS	Study published before 1992
Ciric, I.	1983	USA	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
D’Haens, J.	2009	Belgium	CS	Yes	No	2	PA	ETSS/MTSS	No GTR INFORMATION, THEY REPORTED REMISSION RATE IN FPA NOT GTR AS OUR DEFINATION in the Meta-analysis
Dehdashti, A.	2007	Canada	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION
Esposito, V.	2004	Italy	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
Fatemi, N.	2008	USA	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
Gendeh, B. S.	2006	Kualalumpur	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION
Graham S.M.,	2009	USA	CS	Yes	No	2	PA	ETSS/ Open Pituitary surgery	NO AVAILABLE INFORMATION GTR
Gondim, J.A.	2014	Brazil	CS	Yes	No	1	PA	ETSS	Overlapping cohorts
Gondim, J.A.	2015	Brazil	CS	Yes	No	1	PA	ETSS	Overlapping cohorts
Gondim, J.A.	2010	Brazil	CS	Yes	No	1	PA	ETSS	Overlapping cohorts
Halvorsen, H.	2014	Norway	Cohort	Yes	No	2	PA	ETSS/MTSS	Didn’t design study to report GTR INFORMATION
Higgins, T.S.	2008	United states	Cohort	Yes	No	1	Sellar pathology	MTSS	Not specific for PA
Ho, K. H.	1987	Singapore	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION
Kawamata, T.	2002	Japan	CS	No	Yes	2	PA	EATSS/MTSS	First of all the procedure is EATSS and didn’t design study to report GTR INFORMAT ION / need to check with Hasan
Kim, M.	2009	Korea	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION, only Reported remission rate in Acromegaly
Koren et al.	1999	Israel	CS	Yes	No	2	Pituitary Tumors	ETSS/MTSS	NO AVIALBLE INFORMATION ABOUT GTR
Lu, Y. -J	2009	Taiwan	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION
Minet, W.	2008	Ontario	Cohort	Yes	No	2	Sella-based tumour	EATSS/ETSS	Didn’t design study to report GTR INFORMATION / two group EATSS AND PETSS / NEED TO CHECK?
Nasseri, S.	2001	USA	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION
Neal et al.	2007	USA	Not clear	Yes	No	3	PA	ETSS/MTSS	NO AVAILABLE INFORMATION ABOUT GTR
Patel K.S.	2014	U.S.A.	CS	No	Yes	1	PA	NS	NO AVAILABLE INFORMATION ABOUT GTR
Pinar E.	2015	Turkey	CS	Yes	No	1	PA	ETSS	NO AVAILABLE INFORMATION ABOUT GTR
Prevedello, D. M.	2008	USA	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION, IT report Remission rate in Cushing
Razak, A. A.	2013	UK	Cohort	No	Yes	2	PA	ETSS/MTSS	Didn’t design study to report GTR INFORMATION, IT report Remission rate in FPA
Rudnik, A.	2007	Poland	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION,
Sand, M. S.	2011	Malaysia	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION,
Santos Rde, P.	2007	Brazil	CS	Yes	No	1	Sellar tumors	ETSS	Didn’t design study to report GTR INFORMATION,
Sarkar S.	2016	India	CS	Yes	No	1	PA	ETSS	NO AVAILABLE INFORMATION ABOUT GTR
Semple, P. L	1999	USA	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION,
Senior, B. A.	2008	USA	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION,
Shah S. & Har-El G.	2001	USA	CS	Yes	No				NO AVAILABLE INFORMATION GTR
Shah, S.; Har-El, G.	2001	USA	Cohort	Yes	No	2	PA	ETSS/MTSS	Didn’t design study to report GTR INFORMATION,
Shimon, I	2001	Israel	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION, only Remission rate in Acromegally
Shimon, I.	2002	Israel	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION, only Remission rate in Cushing
Shou, X. -F;	2005	China	CS	Yes	No	1	PA	MTSS	GTR reported but they did more than one type of TSS and result in general we don’t know I how many patient reach to GTR in MTSS or ETSSl
Smith, S. J.	2010	UK	Cohort	Yes	No	2	Skull base	ETSS/MTSS	Didn’t design study to report GTR INFORMATION,
Tindal, G.T.	1978	United states	CS	Yes	No	1	PA	ETSS	Study before 1992
Turner, H. E.	1999	UK	CS	Yes	No	1	Microprolactinomas	MTSS	Didn’t design study to report GTR INFORMATION, only Remission rate in microprolactinoma
Uren, B.	2007	Australia	CS	Yes	No	1	Pituitary Tumors	ETSS	Didn’t design study to report GTR INFORMATION, only Remission rate
Van Bunderen, C.	2013	The Netherland	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION, only Remission rate
Wagenmakers, M.	2013	The Netherland	CS	Yes	Yes	1	PA	ETSS	Didn’t design study to report GTR INFORMAT ION, only Remission rate
Wagenmakers, M.	2011	The Netherland	CS	Yes	No	1	PA	ETSS	Didn’t design study to report GTR INFORMATION, only Remission rate
White et al.	2004	USA	Case control	Yes	No	2	PA	ETSS/MTSS	NO AVAILABLE INFORMATION ABOUT GTR
Yamada S.	2014	Japan	CS	Yes	No	2	PA	ETSS/MTSS	NO AVAILABLE INFORMATION ABOUT GTR
Yamada, S.;	1997	Japan	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION, only Remission rate
Yan Z.	2015	China	CS	Yes	No	1	PA	NS	NO AVAILABLE INFORMATION ABOUT GTR
Zaidi, H.A.	2016	United states	CS	Yes	No	1	PA	ETSS	Patients were operated using iMRI
Zhang, H. W.	2008	China	CS	Yes	No	1	PA	MTSS	Didn’t design study to report GTR INFORMATION, only Remission rate
Zhao, B.	2010	China	CS	Yes	No	1	PA	Extended TSS	Doesn’t meet Criteria because they used Two ETSS/AND in some group MTSS (it called Extended Approach)

CS, Case series; RT, Randomized Trail; ETSS, Endoscopic Transsphenoidal surgery; MTSS, Microscopic Transsphenoidal Surgery; EATSS, Endoscope-Assisted Endonasal Trans-sphenoidal microsurgery; PA, Pituitary Adenomas; GTR, Gross Tumor Resection; NS, Not specified; NA, Not Available; iMRI, intraoperative Magnetic Resonance Imaging

Appendix (3): Analysis of Gross Tumor Resection (GTR) In Pituitary Adenoma Patients according to Tumor Characteristic in the selected studies

Study	Year of Publication	Number of groups	Surgical Intervention	Result of GTR reported for
				PA	Macroaden oma	Microade noma	NF PA	FP A	G H	AC TH	P R L
Bodhinayake et al.4	2014	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Bokhari et al.5	2013	1	ETSS	✔	✔	✔	✔	✔	✔	✔	✔
Campbell et al.6	2010	1	ETSS	✖	✖	✖	✖	✔	✔	✖	✖
Cappabianca et al.7	2002	1	ETSS	✔	✔	✔	✖	✔	✔	✔	✔
Charalampaki et al.8	2009	1	ETSS	✔	✖	✖	✔	✔	✔	✔	✔
Chi et al.9	2013	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Choe et al.10	2008	2	ETSS	✖	✖	✖	✖	✔	✔	✔	✖
			MTSS	✖	✖	✖	✖	✔	✔	✔	✖
Chone et al.11	2014	1	ETSS	✔	✖	✖	✔	✖	✖	✖	✖
Conrad et al.15	2016	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Constantino et al.16	2016	1	ETSS	✔	✔	✖	✖	✖	✖	✖	✖
Cusimano et al.18	2012	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Dallapiazza et al.19	2014	2	ETSS	✖	✖	✖	✔	✖	✖	✖	✖
			MTSS	✖	✖	✖	✔	✖	✖	✖	✖
Dallapiazza et al.20	2015	1	ETSS	✔	✔	✖	✔	✖	✖	✖	✖
Dehdashti et al.23	2008	1	ETSS	✔	✔	✔	✔	✔	✔	✔	✔
De Paiva Neto et al.21	2010	1		✔	✖	✖	✖	✖	✖	✖	✖
De Witte et al.22	2011	1	ETSS	✔	✔	✖	✖	✖	✖	✖	✖
Duz et al.27	2008	2	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
			MTSS	✔	✖	✖	✖	✖	✖	✖	✖
Fathalla et al.30	2015	2	ETSS	✔	✖	✖	✖	✔	✔	✖	✖
			MTSS	✔	✖	✖	✖	✔	✔	✖	✖
Fomekong et al.31	2014	1	MTSS	✔	✔	✖	✖	✖	✖	✖	✖
Frank et al.32	2006	1	ETSS	✖	✖	✖	✔	✖	✖	✖	✖
Gao et al.33	2016	2	ETSS	✔	✔	✔	✖	✖	✖	✖	✖
			MTSS	✔	✔	✔	✖	✖	✖	✖	✖
Gondim et al.35	2011	1	ETSS	✔	✖	✖	✔	✖	✖	✖	✖
Guo-Dong et al.37	2016	2	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
			MTSS	✔	✖	✖	✖	✖	✖	✖	✖
Guvenc et al.38	2016	2	ETSS	✔	✔	✔	✖	✖	✖	✖	✖
			MTSS	✔	✔	✔	✖	✖	✖	✖	✖
Han et al.39	2013	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Hofstetter et al.42	2011	1	ETSS	✖	✔	✔	✖	✔	✔	✔	✔
Jain et al.44	2007	2	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
			MTSS	✔	✖	✖	✖	✖	✖	✖	✖
Jang et al.45	2016	1	ETSS	✔	✖	✖	✔	✖	✔	✔	✔
Jho et al.47	2001	1	ETSS	✖	✖	✖	✔	✖	✖	✖	✖
Juraschka et al.48	2014	1	ETSS	✔	✔	✖	✖	✖	✖	✖	✖
Karppinen et al.50	2015	2	ETSS	✔	✔	✖	✖	✖	✖	✖	✖
			MTSS	✔	✖	✖	✖	✖	✖	✖	✖
Kenan et al.51	2006	1	ETSS	✖	✔	✖	✖	✖	✖	✖	✖
Kuo et al.54	2016	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Kumar et al.53	2012	1	ETSS	✖	✖	✖	✔	✖	✖	✖	✖
Kurosaki et al.55	2000	1	MTSS	✔	✖	✖	✖	✖	✖	✖	✖
Lampropoulos et al.56	2013	1	MTSS	✖	✖	✖	✔	✔	✔	✔	✔
Liu et al.59	2015	1	MTSS	✔	✖	✖	✖	✖	✖	✖	✖
Messerer et al.64	2011	2	ETSS	✖	✖	✖	✔	✖	✖	✖	✖
			MTSS	✖	✖	✖	✔	✖	✖	✖	✖
Mortini et al.67	2005	1	MTSS	✖	✖	✖	✔	✖	✖	✖	✖
Nakao et al.68	2011	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Nie al.69	2015	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Ogawa et al.71	2015	1	MTSS	✔	✖	✖	✖	✖	✖	✖	✖
O’Malley et al.70	2008	2	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
			MTSS	✔	✖	✖	✖	✖	✖	✖	✖
Pinar et al.74	2015	1	ETSS	✔	✔	✔	✖	✖	✖	✖	✖
Qureshi et al.75	2016	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Sheehan et al.78	1999	2	ETSS	✖	✖	✖	✔	✖	✖	✖	✖
			MTSS	✖	✖	✖	✔	✖	✖	✖	✖
Song et al.80	2014	1	ETSS	✔	✖	✖	✖	✔	✖	✖	✖
Thomas et al.82	2014	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Tosaka et al.83	2015	2	ETSS	✔	✔	✖	✖	✖	✖	✖	✖
Wang et al.84	2015	1	ETSS	✔	✔	✔	✖	✖	✖	✖	✖
Wongsirisuwan et al.86	2014	2	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Yan et al.87	2015	1	MTSS	✔	✖	✖	✖	✔	✖	✖	✔
Yildirim et al.88	2016	1	ETSS	✔	✔	✖	✔	✖	✖	✖	✖
Zaidi et al.89	2016	2	ETSS	✖	✖	✖	✔	✖	✖	✖	✖
			MTSS	✖	✖	✖	✔	✖	✖	✖	✖
Zhan et al.90	2015	1	ETSS	✔	✖	✖	✔	✖	✖	✖	✖
Zhang X et al.91	2008	1	ETSS	✔	✖	✖	✖	✖	✖	✖	✖
Zhou et al.92	2014	1	ETSS	✔	✖	✖	✖	✔	✔	✖	✖

ETSS, Endoscopic Transsphenoidal surgery; MTSS, Microscopic Transsphenoidal Surgery; PA, Pituitary Adenomas; GTR, Gross Tumor Resection; NA, No Available; FPA, Functional Pituitary Adenoma; NFPA, Non- Functional Pituitary Adenoma ACTH, Cushing Disease; PRL, Prolactinoma; GH, Growth Hormone Hypersecretion

Appendix 4: Funnel plot for publication bias for overall pituitary adenoma

Appendix 5: Funnel plot for publication bias for functional pituitary adenoma

Appendix 6: Funnel plot for publication bias for non-functional pituitary adenoma