Abstract
Purpose:
The aim of this systematic review is to evaluate the long-term endocrine outcomes and postoperative complications following endoscopic vs. microscopic transsphenoidal resection (TSR) for the treatment of acromegaly.
Methods:
A literature review was performed, and studies with at least five patients who underwent TSR for acromegaly, reporting biochemical remission criteria and long-term remission outcomes were included. Data extracted from each study included surgical technique, perioperative complications, biochemical remission criteria and long-term remission outcomes.
Results:
Fifty-two case series from 1976 to 2016 met the inclusion criteria, comprising 4,375 patients. Thirty-six reports were microsurgical (n=3,144) and thirteen were endoscopic (n=940). Three studies compared microsurgical (n=111) to endoscopic TSR outcomes (n=180). The overall initial and long-term remission rates were 58.2% vs. 57.4% and 69.2% vs. 70.2% for the microsurgical and endoscopic groups, respectively. For microadenomas, the initial and long-term remission rates were 77.6% vs. 82.2% and 76.9% vs. 73.5% for microsurgical and endoscopic approaches, respectively. For macroadenomas, the initial and long-term remission rates were 46.9% vs. 60.0% 40.2% vs. 61.5% for microsurgical and endoscopic approaches, respectively. The rates of postoperative CSF leak were 3.0% vs. 2.3% for the microscopic and endoscopic groups, respectively. The rates of hypopituitarism and transient diabetes insipidus were 6.7% vs. 6.4% and 9.0% vs. 7.8% for the microscopic and endoscopic groups, respectively.
Conclusions:
Both endoscopic and microsurgical approaches for TSR of growth hormone-secreting adenomas are viable treatment options for patients with acromegaly, and yield similarly high rates of remission under the most current consensus criteria.
Keywords: acromegaly, growth hormone, pituitary adenoma, transsphenoidal, endoscopic, microscopic, review
Introduction
Acromegaly, arising from a growth hormone (GH)-secreting pituitary adenoma, is an uncommon disorder that causes significant morbidity and mortality. [1–4] Transsphenoidal resection (TSR), the preferred first-line treatment for acromegaly, has the ability to achieve biochemical and clinical remission upon complete adenoma extirpation, with modest complication rates. [5–9] Significant improvements in life expectancy have been associated with successful adenoma resection. [10]
Microscopic TSR, which has been the mainstay of surgical management over the past fifty years, has since been partially supplanted by the innovation and refinement of the endoscopic technique. [11–20] Although endoscopic TSR has grown in popularity among neurosurgeons, recent series have been generally remiss of large patient cohorts, reporting of operative complications, and comparison of long-term endocrine outcomes to those achieved by microscopic TSR. As such, the optimal surgical approach for the resection of GH-secreting adenomas remains unclear. The aim of this systematic review is to compare the endocrine outcomes and postoperative complication rates of microscopic vs. endoscopic TSR for the treatment of acromegaly.
Methods
Inclusion criteria
Studies qualified for inclusion in the final analysis based on the following criteria: (1) patients with clinical stigmata and biochemical features consistent with a diagnosis of acromegaly; (2) at least five patients who underwent initial or revision TSR; (3) reporting of biochemical remission criteria, and immediate and long-term remission outcomes; and (4) English language. Studies published before the pioneering case series on the endoscopic approach for pituitary adenomas in 1997 were considered microsurgical series by default. [21] Studies published after this date were excluded if the approach was not specified, or if an endoscope was used to augment the microsurgical approach.
Literature Search
No registered review protocol was utilized in this study. This review follows the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. A systematic literature search of the PubMed, Cochrane Library and Embase databases was conducted on June 10, 2017 using the search term: “transsphenoidal AND acromegaly AND adenoma.” Following the search, the articles were then screened by title and abstract. The remaining articles underwent full text review for eligibility, as set forth in the inclusion criteria.
Literature Review and Data Extraction
Included studies were stratified based on their use of a microsurgical or endoscopic technique. Study-specific criteria for biochemical remission were noted and used as the definition of remission. When reported, the following clinical outcomes were extracted: achievement of initial postoperative biochemical remission, perioperative complications, relapse rates, and biochemical remission rates at last follow-up. Perioperative complications included intra- and postoperative cerebrospinal fluid (CSF) leaks, vascular injuries, visual deficits, endocrine abnormalities, meningitis, epistaxis, and transient or permanent diabetes insipidus (DI). In patients who did not achieve initial remission, adjuvant therapy included medical therapy, radiotherapy, stereotactic radiosurgery (SRS), and/or repeat TSR. When information on tumor size was available, patients were further classified into four subgroups: (1) microsurgery-microadenoma, (2) microsurgery-macroadenoma, (3) endoscopy-microadenoma, and (4) endoscopy-macroadenoma. The definition of micro- and macroadenoma was study-specific. Giant adenomas (≥3cm) were classified as macroadenomas.
Statistical Analysis
Statistical analysis was performed using SPSS version 22.0.0 (Armonk, NY: IBM Corp., 2014). Descriptive statistics of pooled data from microsurgical and endoscopic series were obtained for the following outcomes: initial biochemical remission, relapse, biochemical remission at last follow-up, perioperative complications, and adjuvant therapy. Unclear risks of bias were assumed for retrospective studies.
Results
Study selection and characteristics of included studies
The initial screening process resulted in 95 articles, which were further reviewed for data relevance and usability. After application of the inclusion criteria, 43 studies were excluded for the following reasons: use of the endoscope as an adjunct; lack of clear specification of surgical approach used; insufficient reporting of remission criteria, perioperative or long-term outcomes of TSR; overlapping data from the same institution and reporting of data only from patients who achieved initial remission. For the final quantitative analysis, 52 case series, comprising a total of 4,375 patients, were included. Of these series, 36 were microsurgical [12, 22–57] and 13 were endoscopic, [11, 13–18, 58–63], comprising 3,144 and 940 patients, respectively (Figure 1). Three studies compared microsurgical and endoscopic approaches, comprising 111 and 180 patients, respectively.[12, 64, 65] The mean follow-up duration was 61.3 months (Table 1).
Table 1:
Microsurgical Case Series | ||||||||
---|---|---|---|---|---|---|---|---|
Author | Year | Patients, n | Initial Remission, n | Patients with f/u, n |
f/u, mo | Relapse, n |
Remission at last f/u, n |
Remission Criteria |
Fathalla H et al | 2015 | 23 | 8 | 23 | 56.6 | 0 | - | 2010 |
Sarkar S et al | 2014 | 47 | 17 | 47 | 22.38 | 0 | - | 2010 |
Nishioka H et al | 2014 | 150 | 127 | 150 | 22 | 0 | 149 | 2010 |
Sun H et al | 2014 | 59 | 26 | 59 | 13.4 | 0 | 31 | 2010 |
Starke RM et al | 2013 | 41 | 28 | 41 | 18.4 | 0 | 28 | 2010 |
Li ZQ et al | 2012 | 52 | 16 | 49 | 3 | 0 | 16 | 2000 |
Krzentowaka-Korek A et al | 2011 | 85 | 32 | - | - | 0 | - | 2000 |
Shen M et al | 2010 | 39 | 7 | 39 | - | 0 | 8 | 2000 |
Abassioun K et al | 2006 | 151 | 101 | 108 | - | 2 | 99 | Random GH ≤ 10 ng/mL |
Ertruk E et al | 2005 | 30 | 10 | 30 | 42 | 0 | - | Basal or OGTT GH ≤ 2 ng/mL |
Nomikos P et al | 2005 | 506 | 290 | 506 | 146 | 2 | 288 | 2000 |
Kurosaki M et al | 2003 | 22 | 13 | 22 | - | 0 | 13 | Normalized IGF-1, OGTT GH < 1 ng/mL, basal GH < 2.5 ng/mL |
Beauregard C et al | 2003 | 103 | 56 | 95 | - | 4 | 57 | 2000 |
De P et al | 2003 | 90 | 57 | 90 | 130.8 | 0 | 57 | 2000 |
Krieger MD et al | 2003 | 205 | 116 | 181 | 60 | 1 | 116 | Normalized IGF-1, basal GH < 2 ng/mL |
Kreutzer J et al | 2001 | 57 | 40 | 57 | 37.7 | 1 | 41 | 2000 |
Biermasz NR et al | 2000 | 59 | 36 | 59 | 192 | 5 | 58 | 2000 |
Absoch A et al | 1998 | 254 | 193 | 172 | - | 9 | 150 | Basal GH ≤ 5 ng/mL |
Freda PU et al | 1998 | 115 | 70 | 99 | 64.8 | 6 | 82 | Normalized IGF-1 or basal/suppressed GH of ≤ 2 ng/mL |
Yamada S et al | 1997 | 44 | 25 | 39 | 81.6 | 0 | 34 | Normalized IGF-1, basal GH ≤ 3 ng/mL, OGTT GH ≤ 1ng/mL, TRH/ GnRH GH < 10ng/mL |
Sheaves R et al | 1996 | 100 | 42 | 32 | 45.6 | 1 | 31 | Basal GH ≤ 5 ng/mL |
Osman IA et al | 1994 | 79 | 32 | 66 | 85.5 | - | 35 | Basal GH ≤ 5 mU/L and OGTT GH ≤ 2 mU/L |
Tindall GT et al | 1993 | 103 | 85 | 88 | 102 | 0 | 85 | Basal GH ≤ 5 ng/mL, SM-C < 2.2 U/mL |
Buchfelder M et al | 1991 | 61 | 43 | 61 | 72 | 6 | 39 | Basal GH ≤ 5ng/mL and OGTT GH ≤ 2 ng/mL |
Losa M et al | 1989 | 29 | 16 | 25 | - | 0 | 12 | OGTT GH ≤ 1 ng/mL and normalized SM-C |
Fahlbusch R et al | 1988 | 42 | 24 | - | - | - | - | Basal GH ≤ 5 ng/mL |
van’t Verlaat J. et al | 1988 | 25 | 14 | 25 | 42 | 0 | 14 | Basal GH ≤ 5 mU/L; OGTT GH ≤ 4 mU/L; disappearance of TRH responsiveness if present pre-op |
Ross DA et al | 1988 | 214 | 117 | 174 | 76 | 5 | 131 | Basal GH ≤ 5 ng/mL |
Arafah BM et al | 1987 | 43 | 21 | 43 | - | 0 | 21 | Basal GH ≤ 5 ng/mL and normal GH dynamics |
Karashima T et al | 1986 | 44 | 15 | - | - | - | - | Fasting GH ≤ 5 ng/mL and no response to TRH, LHRH, and/or bromocriptine |
Roelfesma F et al | 1985 | 60 | 37 | 60 | 39.6 | - | 48 | Basal GH ≤ 5 mU/L |
Serri O et al | 1985 | 25 | 21 | 25 | 82.8 | 3 | 18 | Basal GH ≤ 5 ng/mL and OGTT GH ≤ 2.5 ng/mL |
Grisoli F et al | 1985 | 100 | 60 | 100 | - | 6 | 56 | Basal GH ≤ 5 ng/mL |
Bynke O et al | 1983 | 14 | 10 | 14 | 27 | 1 | 11 | Basal GH ≤ 5 ng/mL |
Arafah BU et al | 1980 | 25 | 11 | 25 | - | 0 | 11 | Basal GH < 5ng/mL and normal GH dynamics |
Tucker HS et al | 1980 | 32 | 24 | 32 | 48 | 0 | 24 | Basal GH ≤ 5 ng/mL |
Laws ER Jr et al | 1979 | 82 | 34 | 80 | 19 | 1 | 50 | Basal GH ≤ 10 ng/mL |
Leavens ME et al | 1977 | 16 | 10 | 16 | 24 | 0 | 12 | Basal HGH ≤ 10 ng/mL and normal HGH levels after TRH stimulation |
Giovanelli MA et al | 1976 | 29 | 10 | 29 | - | 0 | 17 | Basal GH ≤ 10 ng/mL |
Total | 3255 | 1894 | 2761 | 59.8 | 53 | 1842 | ||
Endoscopic Case series | ||||||||
Netuka D et al | 2016 | 105 | 64 | 105 | 35 | 1 | - | 2010 |
Halioglu O et al | 2016 | 103 | 53 | 103 | 38 | 30 | 77 | 2000 |
Fathalla H et al | 2015 | 42 | 19 | 42 | 56.6 | 0 | - | 2010 |
Sarkar S et al | 2014 | 66 | 19 | 66 | 22.4 | 0 | - | 2010 |
Yildirum A et al | 2014 | 56 | 37 | 56 | 18 | 0 | 53 | 2010 |
Paluzzi A et al | 2014 | 49 | 25 | 49 | 37.3 | 0 | 34 | 2010 |
Zhou T et al | 2014 | 133 | 88 | 114 | - | 0 | 107 | 2000 |
Hazer DB et al | 2013 | 214 | 126 | 214 | 33.16 | 0 | 134 | 2010 |
Starke RM et al | 2013 | 72 | 51 | 72 | 18.4 | 0 | 51 | 2010 |
van Bunderen CC | 2013 | 30 | 9 | 28 | 13.2 | 1 | - | 2000 |
Wang YY et al | 2012 | 43 | 29 | 41 | 34 | 0 | 29 | 2010 |
Dusek T et al | 2011 | 49 | 29 | 49 | 57.12 | 0 | 36 | 2000 |
Wagenmakers MA et al | 2011 | 40 | 20 | 40 | 56 | 2 | 19 | IGF-1 normal for age and sex, OGTT GH < 2 mU/l |
Gondim JA et al | 2010 | 67 | 50 | 67 | 24 | 0 | 54 | 2000 |
Hofstetter CP et al | 2010 | 24 | 9 | 24 | 23.2 | 0 | 11 | 2010 |
Campbell PG et al | 2010 | 27 | 15 | 26 | 24.5 | 0 | 15 | IGF-1 normal for age/sex, OGTT GH < 1ng/mL, random GH < 2.5 ng/mL |
Total | 1120 | 643 | 1096 | 62.7 | 34 | 620 |
Abbreviations: GH = growth hormone; OGTT = oral glucose tolerance test; IGF-1 = insulin-like growth factor 1; GnRH = gondatropin releasing hormone; SM-C = somatomedin C, TRH = thyrotropin releasing hormone, LHRH = lutenizing hormone releasing hormone, n = number, mo = month, f/u = follow up.
Clinical Outcomes
Of the 3,255 patients who underwent microscopic TSR, initial endocrine remission was achieved in 1,894 (58.2%). Follow-up data was available for 2,761 patients, with a mean follow-up interval of 59.8 months. Relapse during the follow-up period occurred in 53 of 1,608 patients (3.3%). At last follow-up, endocrine remission was achieved in 1,842 of 2,661 patients (69.2%). Of the 1,120 patients included in the endoscopic series, initial remission was achieved in 643 (57.4%). Follow-up information was available for 1,096 patients, with a mean follow-up interval of 62.7 months. Relapse occurred in 34 of 546 patients (6.2%), and at last follow-up, remission was achieved in in 620 of 883 patients (70.2%).
Of the microsurgical series that stratified remission and relapse data by tumor size (Table 2), initial remission was achieved in 326 of 420 microadenomas (77.6%) and in 453 of 970 macroadenomas (46.7%). There were no reported relapses in the microadenoma group. However, 10 of 160 macroadenoma patients (1.9%) relapsed. Endocrine remission at last follow-up (Figure 2) was observed in 173 of 225 microadenomas (76.9%) and in 164 of 408 macroadenomas (40.2%).
Table 2:
Microsurgery-Microadenoma | Microsurgery-Macroadenoma | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Author | Year | Patients, n | Initial Remission, n |
Patients with f/u, n |
f/u, mo |
Relapse, n |
Remission at last f/u, n |
Patients, n |
Initial Remission, n |
Patients with f/u, n |
f/u, mo |
Relapse, n |
Remission at last f/u, n |
Starke RM et al | 2013 | 10 | 8 | 10 | 18.4 | 0 | 8 | 31 | 20 | 31 | 18.4 | 0 | 20 |
Krzentowaka-Korek A et al | 2011 | 19 | 17 | - | - | 0 | - | 52 | 16 | 49 | 3 | 0 | 16 |
Li ZQ et al | 2012 | 0 | - | - | - | - | - | 66 | 15 | - | - | - | - |
Ertruk E et al | 2005 | 11 | 7 | 11 | 42 | 0 | - | 39 | 7 | 39 | - | - | 8 |
Shen M et al | 2010 | 0 | - | - | - | - | - | 19 | 3 | 19 | 42 | 0 | - |
Nomikos P et al | 2005 | 142 | 107 | 142 | 146 | - | - | 354 | 182 | 354 | 146 | - | - |
Beauregard C et al | 2003 | 22 | 18 | 22 | - | - | - | 52 | 31 | 52 | - | - | - |
De P et al | 2003 | 29 | 23 | 29 | 130.8 | 0 | 23 | 61 | 34 | 61 | 130.8 | 0 | 34 |
Krieger MD et al | 2003 | 127 | 99 | - | 60 | 0 | 100 | 54 | 17 | - | 60 | 1 | 16 |
Biermasz NR et al | 2000 | 9 | - | 9 | 192 | - | 6 | 50 | - | 50 | 192 | - | 30 |
Freda PU et al | 1998 | 25 | 22 | - | 64.8 | 0 | 23 | 90 | 48 | - | 64.8 | 6 | 59 |
Fahlbusch R et al | 1988 | 4 | 3 | - | - | - | - | 38 | 21 | - | - | - | - |
van’t Verlaat J. et al | 1988 | 8 | 5 | 8 | 42 | 0 | 5 | 17 | 9 | 17 | 42 | 0 | 9 |
Karashima T et al | 1986 | 6 | 3 | - | - | - | - | 38 | 12 | - | - | - | - |
Roelfesma F et al | 1985 | 9 | 6 | 9 | 39.6 | - | - | 42 | 25 | 42 | 39.6 | - | - |
Serri O et al | 1985 | 8 | 8 | 8 | 82.8 | 0 | 8 | 17 | 13 | 17 | 82.8 | 3 | 10 |
Total | 429 | 326 | 248 | 81.8 | 0 | 173 | 1020 | 453 | 731 | 74.7 | 10 | 164 | |
Endoscopy-Microadenoma | Endoscopy-Macroadenoma | ||||||||||||
Netuka D et al | 2016 | 16 | 12 | 16 | 35 | 0 | 13 | 89 | - | - | - | - | - |
Yildirum A et al | 2014 | 5 | 4 | 5 | 18 | 0 | - | 51 | 33 | 51 | 18 | 0 | - |
Palluzzi A et al | 2014 | 5 | 4 | 5 | 37.3 | 0 | 5 | 44 | 21 | 44 | 37.3 | 0 | 29 |
Hazer DB et al | 2013 | 51 | - | 51 | 33.16 | 0 | 32 | 163 | - | 163 | 33.16 | 0 | 102 |
Starke RM et al | 2013 | 13 | 12 | 13 | 18.4 | 0 | 12 | 59 | 39 | 59 | 18.4 | 0 | 39 |
Wang YY et al | 2012 | 13 | 10 | 13 | 34 | 0 | 10 | 30 | 19 | 30 | 34 | 0 | 19 |
Dusek T et al | 2011 | 13 | 10 | 13 | 57.12 | 0 | - | 36 | 19 | 36 | 57.12 | 0 | - |
Wagenmakers MA et al | 2011 | 0 | - | - | - | - | - | 40 | 20 | 40 | 56 | 2 | 19 |
Gondim JA et al | 2010 | 14 | 12 | 14 | 24 | 0 | - | 53 | 38 | 53 | 24 | 0 | - |
Campbell PG et al | 2010 | 4 | 3 | 4 | 24.5 | 0 | 3 | 22 | 12 | 22 | 24.5 | 0 | 12 |
Total | 134 | 67 | 134 | 31.3 | 0 | 75 | 587 | 201 | 498 | 33.6 | 2 | 220 |
Abbreviations: n = number; mo = month; f/u = follow-up.
Of the endoscopic series that stratified remission and relapse data by tumor size (Table 2), initial remission was achieved in 67 of 83 microadenomas (82.2%) and in 201 of 335 macroadenomas (60.0%). There were no reported relapses in the microadenoma group. Relapse occurred in 2 of 242 macroadenoma patients (0.6%). Remission at last follow-up (Figure 2) was observed in 75 of 102 microadenomas (73.5%) and in 220 of 358 macroadenomas (61.5%).
Surgical Complications
For studies that reported intraoperative complications, CSF leak was the most common complication, which occurred in 39 of 1, 373 (2.8%) and 86 of 603 (17.4%) patients who underwent microscopic and endoscopic TSR, respectively (Table 3). The rates of persistent postoperative CSF leak were comparable between the groups, occurring in 3.0% and 2.3% of patients in microscopic and endoscopic groups, respectively. Hypopituitarism and transient DI were the most frequently reported postoperative complications. Hypopituitarism, defined as one or more new endocrine abnormalities, was observed in 191 of 2,542 (6.7%) and 52 of 817 (6.4%) patients in the microscopic and endoscopic groups, respectively. Transient DI was observed in 208 of 2, 492 (9.0%) and in 69 of 889 (7.8%) patients in the microscopic and endoscopic groups, respectively. Permanent DI occurred infrequently, and was reported in 2.0% of microsurgical and 1.7% of endoscopic TSR patients, respectively.
Table 3:
Microsurgical Case Series | |||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Intra-operative complications (n) | Post-operative complications (n) | ||||||||||||
Author | Year | Patients | CSF Leak | Vascular injury |
Visual deficit |
CSF Leak |
Hypopituitarism | Pan- hypopituitarism |
Meningitis | Epistaxis | Transient DI |
Permanent DI |
|
Fathalla H et al | 2015 | 23 | - | - | - | 2 | 1 | - | - | 1 | 8 | 4 | |
Sarkar S et al | 2014 | 14 | 17 | - | 0 | 2 | 18 | 10 | 2 | - | 2 | - | |
Nishioka H et al | 2014 | 150 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
Sun H et al | 2014 | 59 | - | - | - | 0 | - | - | - | - | 6 | 2 | |
Starke RM et al | 2013 | 41 | 12 | 0 | 0 | 1 | - | 0 | 0 | 1 | 2 | 0 | |
Li ZQ et al | 2012 | 52 | - | 0 | 2 | - | 0 | 0 | 0 | 0 | 3 | 1 | |
Krzentowaka-Korek A et al | 2011 | 85 | 0 | 0 | 0 | 0 | - | - | 0 | 0 | 0 | - | |
Shen M et al | 2010 | 39 | - | - | - | - | - | - | - | - | - | - | |
Abassioun K et al | 2006 | 151 | 0 | 0 | 0 | 12 | 28 | 0 | 1 | 0 | 17 | 2 | |
Ertruk E et al | 2005 | 30 | - | 0 | 0 | - | 3 | - | - | 0 | - | - | |
Nomikos P et al | 2005 | 506 | - | 1 | 0 | - | 15 | 0 | - | 0 | 0 | 6 | |
Kurosaki M et al | 2003 | 22 | - | - | - | - | - | - | - | - | - | 0 | |
Beauregard C et al | 2003 | 103 | - | 1 | - | - | 3 | - | - | - | - | - | |
De P et al | 2003 | 90 | - | - | 0 | - | 22 | 39 | 3 | 0 | 16 | 14 | |
Krieger MD et al | 2003 | 205 | - | - | - | - | - | - | - | - | - | - | |
Kreutzer J et al | 2001 | 57 | 0 | 0 | 0 | 1 | 3 | 0 | 0 | - | 2 | 1 | |
Biermasz NR et al | 2000 | 59 | - | - | - | - | 3 | - | - | - | - | - | |
Absoch A et al | 1998 | 254 | 0 | 0 | 0 | 5 | 4 | 0 | 6 | 0 | 54 | 4 | |
Freda PU et al | 1998 | 115 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 0 | |
Yamada S et al | 1997 | 44 | - | 0 | 0 | - | 3 | 1 | 0 | 0 | 21 | 0 | |
Sheaves R et al | 1996 | 100 | - | 1 | 0 | - | 21 | 0 | 8 | 0 | 29 | 8 | |
Osman IA et al | 1994 | 79 | 10 | - | 0 | 0 | 10 | 0 | 0 | 0 | 3 | 0 | |
Tindall GT et al | 1993 | 103 | - | 0 | 1 | - | 3 | 3 | 0 | 0 | 7 | 1 | |
Buchfelder M et al | 1991 | 61 | - | - | - | - | - | - | - | - | - | - | |
Losa M et al | 1989 | 29 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 9 | 0 | |
Fahlbusch R et al | 1988 | 42 | - | - | - | - | - | - | - | - | - | - | |
van’t Verlaat J. et al | 1988 | 25 | 0 | 1 | 0 | 0 | 3 | 2 | 0 | 0 | 2 | 2 | |
Ross DA et al | 1988 | 214 | 0 | 5 | 0 | 11 | 10 | 4 | 4 | 1 | 1 | 0 | |
Arafah BM et al | 1987 | 43 | 0 | 0 | 0 | 0 | - | - | - | - | 10 | 1 | |
Karashima T et al | 1986 | 44 | - | - | - | - | - | - | - | - | - | - | |
Roelfesma F et al | 1985 | 60 | - | - | 2 | - | 17 | 2 | 1 | 0 | 2 | 0 | |
Serri O et al | 1985 | 25 | - | - | - | - | - | - | - | - | - | - | |
Grisoli F et al | 1985 | 100 | - | 2 | - | - | 0 | 0 | - | - | - | - | |
Bynke O et al | 1983 | 14 | 0 | 0 | 0 | 1 | - | - | 0 | 0 | 0 | 0 | |
Arafah BU et al | 1980 | 25 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 4 | 1 | |
Tucker HS et al | 1980 | 32 | 0 | 0 | 0 | 1 | - | 4 | 1 | 0 | 10 | 1 | |
Laws ER Jr et al | 1979 | 82 | - | 0 | 0 | - | 3 | 10 | 0 | 0 | 0 | 0 | |
Leavens ME et al | 1977 | 16 | 0 | 0 | 0 | 5 | 0 | 0 | 1 | 0 | 7 | 0 | |
Giovanelli MA et al | 1976 | 29 | 0 | 0 | 0 | 3 | - | 0 | 0 | 0 | 5 | 0 | |
Total, n/n (%)† | 3222 | 39/1373 (2.8) | 13/2400 (0.5) |
6/2440 (0.2) |
44/ 1455 (3.0) |
191/2542 (6.7) |
76/2368 (3.2) |
27/1861 (1.4) |
4/2349 (0.1) |
208/2492 (9.0) |
48/2375 (2.0) |
||
Endoscopic Series | |||||||||||||
Netuka D et al | 2016 | 105 | - | - | - | 2 | 10 | - | - | - | 1 | - | |
Fathalla H et al | 2015 | 42 | - | - | - | 2 | 1 | - | `- | - | 8 | 4 | |
Sarkar S et al | 2014 | 66 | 22 | - | 0 | 1 | 12 | 14 | - | 1 | 6 | - | |
Yildirum A et al | 2014 | 56 | - | 1 | - | 2 | 1 | 3 | 0 | 0 | 2 | 1 | |
Zhou T et al | 2014 | 133 | 19 | 0 | 1 | 0 | 5 | 3 | 1 | 2 | 12 | 0 | |
Hazer DB et al | 2013 | 214 | 29 | 0 | 0 | 5 | 8 | 1 | 1 | 1 | 0 | 2 | |
Starke RM et al | 2013 | 72 | 23 | 1 | 0 | 2 | - | - | 1 | 4 | 6 | 3 | |
van Bunderen CC | 2013 | 30 | - | - | - | - | - | - | - | - | - | - | |
Wang YY et al | 2012 | 43 | - | 0 | 0 | - | 5 | 0 | 1 | 0 | 14 | 2 | |
Dusek T et al | 2011 | 49 | - | 1 | 0 | - | - | - | 1 | 0 | - | - | |
Wagenmakers MA et al | 2011 | 40 | - | 0 | 0 | 3 | 5 | 0 | 0 | 4 | 15 | 0 | |
Gondim JA et al | 2010 | 67 | 0 | 0 | 0 | 0 | 5 | 0 | 0 | 4 | 3 | 0 | |
Hofstetter CP et al | 2010 | 24 | 12 | 0 | 1 | 2 | 0 | 2 | 0 | 0 | 0 | 0 | |
Campbell PG et al | 2010 | 27 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 | 0 | |
Total, n/n (%)† | 968 | 86/ 603 (17.4) |
3/725 (0.4) |
2/ 735 (0.2) |
20/ 855 (2.3) |
52/ 817 (6.4) |
23/ 670 (3.4) |
5/ 725 (0.7) |
16/791 (2.0) |
69/ 889 (7.8) |
12/ 718 (1.7) | ||
Total n/n = complication / total patients. Abbreviations: Intra-op = intra-operative; post-op = post-operative; CSF = cerebral spinal fluid; DI = diabetes insipidus; n = number.
Adjuvant Therapy
For patients in whom initial remission was not achieved with microscopic TSR (Table 3), 209 of 780 (36.8%) patients received medical therapy, 68 of 867 (7.8%) patients underwent repeat TSR, 263 of 809 (32.5%) patients underwent radiotherapy, and 35 of 867 (4.0%) patients underwent SRS. For patients in whom initial remission was not achieved with endoscopic TSR, 221 of 625 (35.4%) patients received medical therapy, 68 of 611 (11.1%) patients underwent repeat TSR, 26 of 331 (7.9%) patients underwent radiotherapy, and 58 of 492 (11.8%) patients underwent SRS.
Consensus Remission Criteria
Of the microsurgical case series that used the 2000 or 2010 consensus remission criteria, 740 of 1311 (56.4%) patients achieved initial endocrine remission (Figure 3). Relapse occurred in 12 of 841 (1.4%) patients, and long-term remission was achieved in 733 of 1,117 (65.6%) patients. Of the endoscopic case series that used the 2000 or 2010 remission criteria, 608 of 1,053 (57.7%) patients achieved initial remission. Relapse occurred in 32 of 512 (0.6%) patients, and long-term remission was achieved in 576 of 789 (73.0%) patients.
Of the microsurgical series which stratified outcomes by tumor size and using the 2000 or 2010 criteria (Figure 3), 173 of 222 microadenomas (77.9%) and in 301 of 636 macroadenomas (47.4%) achieved initial remission. No relapses were observed in either group. Long-term remission was reported in 37 of 48 microadenomas (77.1%) and in 100 of 191 macroadenomas (52.4%). Of the endoscopic series which stratified outcomes by tumor size and using the 2000 or 2010 criteria, initial remission was achieved in 64 of 79 microadenomas (81.0%) and in 210 of 273 macroadenomas (76.9%). No relapses occurred in either group. Long-term remission was reported in 40 of 47 microadenomas (85.1%) and in 87 of 133 macroadenomas (65.4%).
Discussion
Systemic elevation of GH and IGF-1 levels in patients with acromegaly is associated with significant morbidity and mortality. With the advent of novel therapies, the potential to increase life expectancy and achieve therapeutic remission in patients with a wide spectrum of clinical and radiographic disease burden has grown.[10] TSR, which can rapidly normalize hormone levels and provide relief from mass effect, is currently favored over medical therapy. [7, 12, 66, 67] The earliest transsphenoidal approaches to the pituitary made use of the microscope to effectively visualize the operative field. [68, 69] The endoscopic-assisted transsphenoidal approach, introduced in 1963 by Guiot et al, refers to the use of the endoscope as an adjunct to the microscopic removal of a tumor. [70] Although this approach was succeeded, in the 1990’s, by the pure endoscopic transsphenoidal approach, a recent series has highlighted the utility of the endoscopic-assisted technique for its ability to achieve additional adenoma removal following maximal microscopic resection of large and invasive tumors. [71, 72]
Further refinement of the pure endoscopic approach has led to its popularization, in some institutions, over the microscopic approach. However, optimal treatment protocols for patients with acromegaly remain unclear, due to a lack of long-term follow-up and comparison of remission outcomes between surgical modalities, in recent series. [12] Previous reports of endoscopic TSR for acromegaly have been limited by small cohort sizes, short durations of clinical and/or radiographic follow-up, and lack of a uniform definition of remission.[12]
Recent series have advocated for surgical decisions regarding approach to be based upon tumor size and position, preferring microscopic TSR for small, and endoscopic for large tumors.[73] The relative advantages afforded by the endoscope are that it offers a wider, more panoramic view, enabling better visualization and control of the lateral aspects of the tumor and operative field, including views into the suprasellar compartment and lateral aspect of cavernous sinus. However, the disadvantages of the endoscope are that it does not offer three-dimensional stereotactic images like those obtained with the operative microscope, and its surgical instruments have limited maneuverability. [12] The recent development and uptake of three-dimensional endoscopes into clinical practice may, in the imminent future, offset these current disadvantages [74]. Intra-operative MRI, which has been used as an adjunct to both microsurgical and endoscopic techniques, provides an early objective assessment of the radicality of tumor resection [75]. With its use, an improvement in surgical outcomes and consequent remission rates has been reported in two microsurgical and two endoscopic case series [62, 76–78]. Greater accessibility to this technology may, therefore, lead to increased application in the resection of GH-secreting pituitary adenomas.
This review found overall initial and long-term remission rates to be comparable between the endoscopic and microscopic approaches. Better outcomes were achieved for microadenomas, irrespective of surgical modality. Highlighting the relevance of tumor size to the appropriateness of surgical approach, use of the endoscopic technique may achieve higher initial and long-term remission rates in patients with macroadenomas, providing emphasis to the potential benefit of this approach for large tumors. Our findings are consistent with recent analyses suggesting that remission rates achieved by TSR are generally higher for GH-secreting microadenomas, but that endoscopic TSR may achieve improved rates of complete tumor resection and biochemical remission for macroadenomas. [79–81]
Adjuvant therapy, which includes hormone-suppressant medication, repeat surgery, SRS or radiotherapy, plays an important role in the long-term management of patients who do not attain immediate remission following TSR. [82, 83] Although the rates of adjuvant medical therapy were comparable between the two groups, radiotherapy was more frequently employed following microsurgical (32.5%) than endoscopic (7.9%) TSR. This may be due to the fact that the more recently published case series reporting the endoscopic approach correspond with an increasing popularization of adjuvant SRS over radiotherapy. [84] Although there was a high rate of intra-operative CSF leak observed in the endoscopic group (17.4%), rates of persistent CSF leak and postoperative endocrine complications were comparable between the two groups.
Based on updated 2010 consensus guidelines for remission from acromegaly, high rates of biochemical remission, ranging from 77–87% in patients with microadenomas and 63–66% in patients with macroadenomas, have been achieved with the use of endoscopic TSR. [12, 14] That the majority of patients do achieve remission holds promise, relative to prior series reporting a wider variety of outcomes. Under the less strict biochemical criteria of the 2000 consensus report, remission rates ranged from 42%–72% with microsurgery and 56%–83% with endoscopy. [16–18, 23, 26, 28, 67, 85–98] Although the results from this review are largely consistent with the most recent reports, we have observed higher long-term remission rates for macroadenoma resection with the use of the endoscopic technique.
Different surgical approaches offer unique balances of advantages and limitations, but none are immune to the challenges of complete resection of large and laterally localized tumors. For any surgical approach, the utility of the Knosp grade as a preoperative predictor of outcome has been emphasized.[12, 25, 26, 66, 99–102] It is well established that Knosp grade 3 or 4 tumors are associated with significantly lower rates of complete resection and biochemical remission.[7, 12, 26, 99] In some series, the Knosp grade has been shown to be even more predictive of postoperative remission than size for acromegaly patients.[13, 17, 18, 88, 103–105] The potential for the endoscopic technique to achieve a better visualization of the operative field and a more complete resection, in cases of cavernous sinus invasion, should, therefore, be further investigated. It should also be noted that patients treated in higher volume centers have better overall outcomes, lending credence to the benefit of surgeon experience, regardless of surgical approach.[12, 14, 28, 106, 107]
The present study’s strengths include the large number of patients and longitudinal nature of follow-up of the included case series. However, there are several important limitations of the study which should be noted. The comparison of results between endoscopic and microsurgical series was based on a summation of data from a heterogeneous cohort of patients, with differences in the number of cases and duration of follow-up between each group. Definitions for the diagnosis of acromegaly and biochemical remission were not consistent between studies. Older studies may be limited by early imaging techniques. Furthermore, operator expertise in either technique can dramatically influence patient outcomes and studies intending to compare the two approaches may have strong inherent biases. Hence, a true objective comparison may never be achieved, and the limited number of studies directly comparing approaches has precluded a meta-analysis from being performed.
Conclusions
Both endoscopic and microsurgical approaches for TSR provide viable treatment options for patients with acromegaly, yielding similarly high rates of endocrine remission under the most current consensus criteria without observed differences in postoperative complications. Higher rates of remission were achieved for microadenomas, irrespective of surgical modality. The endoscopic approach may offer a benefit in the resection of macroadenomas, where the greater field of view affords a greater potential for complete extirpation. However, surgeon expertise and familiarity with each of the techniques are likely to concurrently affect outcomes. Due to limitations in the literature, a direct comparison between the approaches cannot be carried out, and therefore, further studies directly comparing endoscopic and microsurgical approaches are warranted, in order to further clarify their respective advantages in the surgical management of acromegaly.
Table 4:
Microsurgical Series | |||||||||
---|---|---|---|---|---|---|---|---|---|
Author | Year | Patients requiring medical therapy, n/n |
Patients requiring repeat surgery, n/n |
Patients requiring radiotherapy, n/n |
Patients requiring radiosurgery, n/n |
||||
Nishioka H et al | 2014 | 15/150 | 0/150 | 4/150 | 0/150 | ||||
Starke RM et al | 2013 | 7/13 | 0/13 | 2/13 | 6/13 | ||||
Krzentowaka-Korek A et al | 2011 | 53/53 | 0/53 | 0/53 | 0/53 | ||||
Shen M et al | 2010 | 0/32 | 0/32 | 0/32 | 11/32 | ||||
Abassioun K et al | 2006 | 0/7 | 0/7 | - | 0/7 | ||||
Ertruk E et al | 2005 | 13/20 | 6/20 | 8/20 | 3/20 | ||||
Kurosaki M et al | 2003 | 8/9 | 0/9 | 0/9 | 3/9 | ||||
Beauregard C et al | 2003 | 5/47 | 10/47 | 12/47 | 0/47 | ||||
De P et al | 2003 | 33/33 | 0/33 | 31/33 | 0/33 | ||||
Kreutzer J et al | 2001 | 13/17 | 1/17 | 0/17 | 10/17 | ||||
Biermasz NR et al | 2000 | 6/23 | 0/23 | 19/23 | 0/23 | ||||
Absoch A et al | 1998 | 7/61 | 3/61 | 24/61 | 0/61 | ||||
Freda PU et al | 1998 | 15/45 | 12/45 | 30/45 | 2/45 | ||||
Yamada S et al | 1997 | 1/19 | 0/19 | 0/19 | 0/19 | ||||
Sheaves R et al | 1996 | 0/58 | 0/58 | 0/58 | 0/58 | ||||
Osman IA et al | 1994 | 0/47 | 9/47 | - | 0/47 | ||||
Tindall GT et al | 1993 | 13/18 | 0/18 | 12/18 | 0/18 | ||||
Losa M et al | 1989 | 9/9 | 3/9 | 2/9 | 0/9 | ||||
van’t Verlaat J. et al | 1988 | 11/11 | 0/11 | 11/11 | 0/11 | ||||
Ross DA et al | 1988 | - | 7/87 | 38/87 | 0/87 | ||||
Roelfesma F et al | 1985 | 0/23 | 2/23 | 19/23 | 0/23 | ||||
Bynke O et al | 1983 | 0/4 | 2/4 | - | 0/4 | ||||
Tucker HS et al | 1980 | 0/8 | 3/8 | 5/8 | 0/8 | ||||
Laws ER Jr et al | 1979 | 0/48 | 3/48 | 27/48 | 0/48 | ||||
Leavens ME et al | 1977 | 0/6 | 4/6 | 2/6 | 0/6 | ||||
Giovanelli MA et al | 1976 | 0/19 | 3/19 | 17/19 | 0/19 | ||||
Total, n/n (%†) | 209/780 (26.8 %) |
68/867 (7.8 %) |
263/809 (32.5 %) |
35/867 (4.0 %) |
|||||
Endoscopic Series | |||||||||
Netuka D et al | 2016 | 24/105 | 7/105 | - | 32/105 | ||||
Halioglu O et al | 2016 | 70/103 | 9/103 | 9/103 | 0/103 | ||||
Yildirum A et al | 2014 | 19/56 | 16/56 | - | 3/56 | ||||
Zhou T et al | 2014 | 23/133 | 4/133 | - | - | ||||
Hazer DB et al | 2013 | 0/88 | 22/88 | 0/88 | 0/88 | ||||
Starke RM et al | 2013 | 11/21 | 0/21 | 6/21 | 9/21 | ||||
van Bunderen CC | 2013 | 16/21 | 4/21 | 1/21 | 0/21 | ||||
Wang YY et al | 2012 | 12/14 | - | 4/14 | 0/14 | ||||
Dusek T et al | 2011 | 14/20 | 0/20 | 0/20 | 5/20 | ||||
Wagenmakers MA et al | 2011 | 14/20 | 2/20 | 6/20 | 2/20 | ||||
Gondim JA et al | 2010 | 0/17 | 4/17 | 0/17 | 0/17 | ||||
Hofstetter CP et al | 2010 | 9/15 | 0/15 | 0/15 | 5/15 | ||||
Campbell PG et al | 2010 | 9/12 | 0/12 | 0/12 | 2/12 | ||||
Total, n/n (%)† | 221/625(35.4%) | 68/611(11.1%) | 26/331 (7.9 %) | 58/492(11.8 %) | |||||
Abbreviations: n = number.
Total n/n = patients receiving adjuvant therapy after surgery / patients not in remission after initial surgery
Acknowledgments
Funding: No funding was received for this research.
Abbreviations:
- TSR
transsphenoidal resection
- GH
growth hormone
- PRISMA
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
- CSF
cerebral spinal fluid
- DI
diabetes insipidus
- SRS
stereotactic radiosurgery
Footnotes
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent: For this type of study formal consent is not required. This article does not contain any studies with human participants performed by any of the authors.
Conflict of Interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
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