Gastrointestinal stromal tumors (GISTs), although rare, are the most common nonepithelial neoplasm of the gastrointestinal tract. Approximately, 95% of GISTs express the KIT receptor tyrosine kinase, and approximately 80% of GISTs have KIT gene mutations. GISTs might arise anywhere along the gut, with the most common sites being stomach (50–70%) and small intestine (35%). Surgery is the only potentially curative therapy for patients with primary, resectable GISTs. Complete resection of the tumor without lymphadenectomy is recommended since lymph node metastases are rare.
Since the development of minimally invasive surgical approaches, laparoscopic surgery (LAP) for GISTs has evolved rapidly over the past decade. Various clinical studies and meta-analysis have demonstrated that LAP for GISTs of the stomach had associated with lesser pain, shorter hospital stay, faster postoperative recovery, lower morbidity, and similar recurrence rates compared to open approach (OPEN). However, there is a paucity in the literature on the management and outcomes of laparoscopic small bowel GISTs resection due to relatively low incidence rate. Therefore, the reliable short-term outcomes following LAP for small bowel GISTs are unknown. Besides, whether the oncologic benefits observed in laparoscopic gastric GISTs resection could also apply to intestine need more research to confirm. In recent years, there have been some reports, which compared outcomes between LAP and OPEN for small bowel GISTs, the majority based on small series of patients and retrospective analyses. Therefore, we present a systematic review and meta-analysis of the literature to assess accurately the current status of LAP for small bowel GISTs.
The systematic searches of Web of Science, Cochrane Library, Embase, and PubMed were conducted in order to find the theses which have been published till the end of 2016 and conducted comparison between LAP and OPEN. The search terms “gastrointestinal stromal tumor,” “GIST,” “submucosal tumors,” “SMT,” “laparoscopic,” “laparoscopy,” “enterectomy,” “bowel,” “intestine,” “jejunum,” “ileum,” and “gut” were utilized. The linkages of search results and references in the identified original thesis could be reviewed to find the extra literature which has not been indexed. The language of all publications was limited to English only.
Quality assessment and data collection
Researches that meet the below standards were comparative, peer-reviewed studies of LAP versus OPEN on intestinal GISTs which were available in the full text of the thesis. All procedures were peer-reviewed by two reviewers independently. The articles including any of the following were excluded: (1) noncomparative studies such as letters, reviews, comments, posters, protocols, and overlap authors or centers; (2) studies including tumors outside small bowel; (3) studies that included emergency operation cases; (4) studies in which <2 of the interesting indices were reported, or it was difficult to calculate these from the outcomes. The Newcastle-Ottawa Quality Assessment Scale (NOS) was utilized to evaluate the quality of the researches included. The scale changes from 0 to 9 stars: researches with a score higher than or equal to 6 could be deemed as good methodological. Any disagreement in quality assessment and data collection was discussed and solved using a third party as the referee. The general information extracted included region, publication year, journal, sample size, operation time, estimated blood loss (EBL), time to flatus, time to oral intake, length of hospital stay (LOS), morbidity, mortality, and long-term outcomes.
Continuous variables were assessed using the weighted mean difference (WMD), and dichotomous variables were analyzed using the risk ratio (RR). If the study provided medians and ranges instead of means and standard deviations (SDs), we estimated the means and SDs as described by Hozo et al. Statistical heterogeneity, which indicated between-study variance, was evaluated according to the Higgins I2 statistic. To account for clinical heterogeneity, which refers to diversity in a sense that is relevant for clinical situations, we used the random-effects model based on DerSimonian and Laird's method. Potential publication bias was determined by conducting informal visual inspection of funnel plots based on the complications. Data analyses were performed using RevMan 5.1 software (Cochrane Collaboration, Oxford, UK) downloaded from Cochrane Library. A value of P < 0.05 was considered statistically significant.
Search and selection
The initial search strategy retrieved 386 publications in English. After the titles and abstracts were reviewed, articles without comparison of LAP and OPEN for intestinal GISTs were excluded, which left nine comparative studies, three of which did not meet the inclusion criteria and were excluded because of including tumors outside small bowel. This left six observational studies, all of which were accessible in full-text format. Search and selection flowchart is illustrated in Figure 1.
Study characteristics and quality
A total of 391 patients were included in the analysis with 170 undergoing LAP (43.5%) and 221 undergoing OPEN (56.5%). They represented only East Asia experience (one Korea, two Mainland of China, two Chinese Taiwan, and one Chinese Hong Kong). Table 1 presents the characteristics of the included studies, and Table 2 presents the quality assessment based on the NOS, whereas the outcomes reported by the included studies are shown in Table 3. According to the NOS, one article got 8 stars and the remaining five got 9 stars.
The tumor location and laparoscopic technical details and reasons for conversion of included studies are summarized in Table 4. All intraoperative outcomes are summarized in Table 5. The mean operation time of LAP was 27.97 min shorter than for OPEN (WMD = −27.97 min; 95% confidence interval [CI]: −49.40–−6.54, P < 0.01, Figure 2a). Intraoperative EBL during surgery was decreased during the laparoscopic procedure (WMD = −0.72 ml; 95% CI: −1.30–−0.13, P = 0.02, Figure 2b). The length of abdominal incision was significantly short in LAP patients (WMD = −10.08 cm; 95% CI: −10.66–−9.49, P < 0.01, Figure 2c). Although individual included studies did not report significant difference in tumor size, the pooled data showed that the tumor size in LAP group was significantly smaller than that in OPEN from the analysis of 391 resections (WMD = −0.82 cm; 95% CI: −1.52–−0.12, P = 0.02, Figure 2d).
Postoperative clinical course
All postoperative outcomes are summarized in Table 5. Postoperative pain was evaluated by the number of days of analgesic use or the dosage of analgesic. Tsui et al. reported less morphine consumption, whereas Liao et al. reported shorter duration of analgesia in LAP group. The mean time of first flatus was shorter in LAP than that in OPEN (WMD = −0.83 day; 95% CI: −1.44–−0.22, P < 0.01, Figure 3a) as was the time to restart oral intake after surgery (WMD = −1.95 days; 95% CI: −3.31–−0.60, P < 0.01, Figure 3b). Moreover, LOS was 3 days shorter for LAP patients (WMD = −3.00 days; 95% CI: −4.87–−1.13, P < 0.01, Figure 3c). Besides, Cai et al. documented a reduced hospital costs in LAP group regardless of surgical or medical charges.
Mortality was described only in two studies. Ihn et al. reported a dead case in LAP group due to bleeding secondary to recurrent anastomosis leakages, while Liao et al. reported another dead case in OPEN group because of profound sepsis. The pooled data showed that there was no significant difference in postoperative mortality (RR = 1.70, 95% CI: 0.18–16.04, P = 0.64, Figure 3d). Besides, Tsui et al. reported two reoperation cases in LAP group due to intestinal obstruction. The specific postoperative complications included in the studies are summarized in Table 6. The rate of overall postoperative complications was lower for LAP with a significant difference (RR = 0.56, 95% CI: 0.33–0.97, P = 0.04, Figure 3e).
Oncologic outcomes and long-term survival
Liao et al. reported 2 (8.7%) cases of microscopic rupture in LAP group and 6 (13.6%) cases in OPEN group. They also found 2 (3.4%) cases of tumor spillage in OPEN group. Other studies reported no case of spillage or rupture with negative surgical margin involved. Besides, Cai et al. reported no differences in distances from the upper or lower margin between two groups.
During the follow-up, tumor recurrence was observed in all six studies. Cai et al. only reported a total of ten recurrence cases in two groups but failed to indicate respective ones between groups. The difference between LAP and OPEN about recurrence was not statistically significant (recurrence diagnosis = −0.06, 95% CI: −0.16–0.05, P = 0.28, Figure 4a). Four studies reported postoperative survival rates, all of which did not find significant differences in survival rates between groups. Although Ihn et al. did not report specific survival rate, they also found no significant difference in the survival rates between the two groups during their follow-up time. Meta-analysis of these available data demonstrated that the 3-year disease-free survival (DFS) rate was not significantly different in participants who received LAP compared with OPEN (RR = 1.13, 95% CI: 0.91–1.39, P = 0.27, Figure 4b). However, the meta-analysis of another survival rate cannot be done due to limited data. The available data about recurrence patterns, specific recurrent sites, and survival outcomes are summarized in Table 7.
A funnel plot analysis of total postoperative complications was performed. It was shown that none of the studies were outside the limits of 95% CI, and there was no evidence of publication bias [Figure 5].
The main reason why most minimally invasive abdominal surgeries such as laparoscopic gastrectomy, colorectectomy, and pancreaticoduodenectomy need longer operation time compared to open ones is the necessity of complicated lymphadenectomy under laparoscopy. However, LAP for small bowel GISTs need no lymph node dissection, while avoids cutting and suturing of the long abdominal incision, thus leading to a shorter operation time. The intraoperative bleeding in the LAP group was less than that in the OPEN group, similar to most reports comparing laparoscopic and open surgery. The reduced length of incision wound and the application of energy-dividing devices contribute to the reduction in blood loss. However, this result should be interpreted prudently due to the high heterogeneity between studies as a result of different methods of estimating blood loss. It was conceivable that complications were similar between groups because LAP results in the same organ as OPEN [Table 6]. Nevertheless, it is should be noted that two included studies reported cases of occurring intestinal obstruction after LAP. Wan et al. presumed that postoperative anastomotic swelling and intra-abdominal adhesion were probably the main causes of postoperative intestinal obstructions. Patients received LAP was associated with less pain, as well as shorter surgical duration and lower dosage of analgesic application than OPEN. The time to first flatus was also earlier in LAP group, indicating a rapid recovery of gastrointestinal function after LAP. Smaller incisions of abdominal cavity, lower usage of paregoric, and earlier postoperative activities are thought to be the main reasons for faster recovery from LAP.
The adequacy of the radical resection should be evaluated not only by margin status but also by complete resection without tumor spillage or rupture. In addition to the included studies with a lower rate of tumor rupture, Tabrizian et al. reported no evidence of tumor spillage or rupture and achieved an R0 resection in 97.4% of cases based on their 26 cases of intestinal GISTs. In our view, LAP is in accordance with the “no touch tumor” principle as open surgery and even might be better. Tumor can be resected in situ, thus avoiding stressing on the tumor. Even for tumor failed to be resected totally laparoscopically, the operation can be accomplished in mini-laparotomy after fully mobilization of tumor. Compared with gastric GISTs, small bowel tumors with similar size and mitotic index had a markedly worse prognosis in a large series with decreased recurrence-free survival rate. Based on the available data, postoperative recurrence and the long-term survival rate in LAP were similar to those in OPEN. Tabrizian et al. analyzed the results of 26 cases of small bowel GISTs treated with LAP with a median follow-up of 56.4 months (range 0.1–162.4 months). The 10-year overall survival rate and DFS rate were 91.3% and 71.6%, respectively. It seems that laparoscopy as a minimally invasive intervention provides a similar long-term outcome for GIST tumors compared to open surgery. Therefore, we believed that the pathological presentation of the tumor, particularly tumor size and mitotic rate, was a more critical factor that influenced recurrence, rather than the operative technique. In recent years, the development of imatinib has led to modifications in the standard care for GISTs in many places around the world.
Small bowel GISTs had a more acute presentation requiring emergent resections secondary to hemorrhage, obstruction, or perforation. Zang et al. reported 77 cases small intestinal bleeding treatment by laparoscopic surgery, in which neoplasm is the most frequent cause of small intestinal bleeding (48 GISTs cases, 62.3%). Thinks to the ability of inspecting the whole intestinal serosa and mesentery thoroughly, it is logical to assume that laparoscopic exploration can avoid the omission of multiple synchronous lesions. They recommended that laparoscopic wedge resection was performed when the tumor size is smaller than 1 cm, whereas segmental resection was used for the bigger lesions. Therefore, laparoscopic technique could achieve good therapeutic outcomes and improve diagnostic chance in small intestinal diseases. Obstruction was less common than bleeding. Morrison and Hodgdon reported two cases of small bowel GISTs presented with obstructive symptoms and were treated laparoscopically. They summed up the elements to the success of such operation, these were early intervention, accurate entry to the abdominal cavity, higher pressure for insufflation, appropriate position of patients and location of trocars, dissection from the distal ileum back to the lesion, and grasp the mesentery instead of the bowel. Besides, it is accepted that the leakage rate will increase if the anastomosis done with a stapler when the bowel wall is thickened. Therefore, hand-sewn extracorporeal anastomosis is recommended in these instances.
Combined with literature and our practice, we have summarized some surgical experience. First of all, to avoid tumor rupture or spillage, the oncological principles are same as open surgery, including no tumor touch, adequate margins, and en bloc resection without lymphadenectomy. Tabrizian et al. summarized that the factors associated with failure of LAP were extensive adhesions, preoperative tumor perforation, proximity to the duodenum, extent of disease, or concomitant resection of other malignant lesions, which were similar to the conversion reasons in our included studies [Table 4]. GISTs are often in oval shape and hypogastrium wall has more ductility, making specimen being delivered through a bit smaller incision size than shortest diameter of the mass. Because of the mobility of the small intestine, the bowel could be able to pull out from the umbilical incision. Therefore, we recommend extracorporeal anastomosis under direct vision instead of intracorporeal one to reduce the operation time and lower the learning curve of this procedure, making it accessible to novice laparoscopic surgeons. Extracorporeal anastomoses also save the charge of anastomotic staplers. We should not ignore the fact that small bowel GISTs were incidentally found during the workup of other diseases or other operations. Therefore, one point should be deeply rooted in mind that careful abdominal exploration is essential when performing other abdominal operations.
The results of this meta-analysis should be interpreted with caution for several limitations. First, none of the included studies are randomized, and the overall level of clinical evidence is low. Hence, these results are only an estimate of the true benefit of LAP for small bowel GISTs. Significant heterogeneity existed among the studies, so we applied a random-effects model to take between-study variation into consideration. Second, there was inevitably a selection bias in the published literature. Although individual included studies did not report significant difference in tumor size, the pooled data showed that the tumor size for LAP was significantly smaller than that for OPEN, which will tend to favor laparoscopic technique. Third, there were a relatively small number of studies and sample size, as well as regional differences. Therefore, we included studies which a small proportion of other type gastric submucosal tumors (SMTs). It is critical that getting sample size large enough to detect a possible treatment effect, especially for some issues with few studies. Considering the surgical strategies of SMTs are similar, we did not exclude the studies including a small proportion of other SMTs. Even through such a few cases does not result in a significant bias, it still can lead to clinical heterogeneity.
In conclusion, the results of this meta-analysis favor the safety and efficacy of LAP compared with OPEN for small bowel GISTs. However, given the aforementioned limitations, more evidence of multicenter RCTs is needed to further address the real role of laparoscopic technique.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Huang J, Zhang B, Huang LY. Screening for differentially expressed genes of gastric stromal tumor originating from muscularis propria Chin Med J. 2017;130:737–40 doi: 10.4103/0366-6999.201614
2. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival Ann Surg. 2000;231:51–8
3. Wu CR, Huang LY, Guo J, Zhang B, Cui J, Sun CM, et al Clinical control study of endoscopic full-thickness resection and laparoscopic surgery in the treatment of gastric tumors arising from the muscularis propria Chin Med J. 2015;128:1455–9 doi: 10.4103/0366-6999.157651
4. Cai JQ, Chen K, Mou YP, Pan Y, Xu XW, Zhou YC, et al Laparoscopic versus open wedge resection for gastrointestinal stromal tumors of the stomach: A single-center 8-year retrospective cohort study of 156 patients with long-term follow-up BMC Surg. 2015;15:58 doi: 10.1186/s12893-015-0040-2
5. Dressler JA, Palazzo F, Berger AC, Stake S, Chaudhary A, Chojnacki KA, et al Long-term functional outcomes of laparoscopic resection for gastric gastrointestinal stromal tumors Surg Endosc. 2016;30:1592–8 doi: 10.1007/s00464-015-4384-6
6. Piessen G, Lefèvre JH, Cabau M, Duhamel A, Behal H, Perniceni T, et al Laparoscopic versus open surgery for gastric gastrointestinal stromal tumors: What is the impact on postoperative outcome and oncologic results? Ann Surg. 2015;262:831–9 doi: 10.1097/SLA.0000000000001488
7. Chen K, Zhou YC, Mou YP, Xu XW, Jin WW, Ajoodhea H. Systematic review and meta-analysis
of safety and efficacy of laparoscopic resection for gastrointestinal stromal tumors of the stomach Surg Endosc. 2015;29:355–67 doi: 10.1007/s00464-014-3676-6
8. Grover S, Ashley SW, Raut CP. Small intestine gastrointestinal stromal tumors Curr Opin Gastroenterol. 2012;28:113–23 doi: 10.1097/MOG.0b013e32834ec154
9. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample BMC Med Res Methodol. 2005;5:13 doi: 10.1186/1471-2288-5-
10. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses BMJ. 2003;327:557–60 doi: 10.1136/bmj.327.7414.557
11. Basu S, Balaji S, Bennett DH, Davies N. Gastrointestinal stromal tumors (GIST) and laparoscopic resection Surg Endosc. 2007;21:1685–9 doi: 10.1007/s00464-007-9445-z
12. Chen YH, Liu KH, Yeh CN, Hsu JT, Liu YY, Tsai CY, et al Laparoscopic resection of gastrointestinal stromal tumors: Safe, efficient, and comparable oncologic outcomes J Laparoendosc Adv Surg Tech A. 2012;22:758–63 doi: 10.1089/lap.2012.0115
13. Fisher SB, Kim SC, Kooby DA, Cardona K, Russell MC, Delman KA, et al Gastrointestinal stromal tumors: A single institution experience of 176 surgical patients Am Surg. 2013;79:657–65
14. Tsui DK, Tang CN, Ha JP, Li MK. Laparoscopic approach for small bowel tumors Surg Laparosc Endosc Percutan Tech. 2008;18:556–60 doi: 10.1097/SLE.0b013e3181889d25
15. Huang CC, Yang CY, Wu MH, Wang MY, Yeh CC, Lai IR, et al Gasless laparoscopy
-assisted versus open resection of small bowel lesions J Laparoendosc Adv Surg Tech A. 2010;20:699–703 doi: 10.1089/lap.2009.0417
16. Cai W, Wang ZT, Wu L, Zhong J, Zheng MH. Laparoscopically assisted resections of small bowel stromal tumors are safe and effective J Dig Dis. 2011;12:443–7 doi: 10.1111/j.1751-2980.2011.00536.x
17. Ihn K, Hyung WJ, Kim HI, An JY, Kim JW, Cheong JH, et al Treatment results of small intestinal gastrointestinal stromal tumors less than 10 cm in diameter: A comparison between laparoscopy
and open surgery J Gastric Cancer. 2012;12:243–8 doi: 10.5230/jgc.2012.12.4.243
18. Wan P, Li C, Yan M, Yan C, Zhu ZG. Laparoscopy
-assisted versus open surgery for gastrointestinal stromal tumors of jejunum and ileum: Perioperative outcomes and long-term follow-up experience Am Surg. 2012;78:1399–404
19. Liao CH, Yeh CN, Wang SY, Fu CY, Tsai CY, Liu YY, et al Surgical option for intestinal gastrointestinal stromal tumors – Perioperative and oncological outcomes of laparoscopic surgery Anticancer Res. 2015;35:1033–40
20. Chen K, Pan Y, Cai JQ, Xu XW, Wu D, Mou YP. Totally laparoscopic gastrectomy for gastric cancer: A systematic review and meta-analysis
of outcomes compared with open surgery World J Gastroenterol. 2014;20:15867–78 doi: 10.3748/wjg.v20.i42.15867
21. Reza MM, Blasco JA, Andradas E, Cantero R, Mayol J. Systematic review of laparoscopic versus open surgery for colorectal cancer Br J Surg. 2006;93:921–8 doi: 10.1002/bjs.5430
22. Strijker M, van Santvoort HC, Besselink MG, van Hillegersberg R, Borel Rinkes IH, Vriens MR, et al Robot-assisted pancreatic surgery: A systematic review of the literature HPB (Oxford). 2013;15:1–10 doi: 10.1111/j.1477-2574.2012.00589.x
23. Tabrizian P, Sweeney RE, Uhr JH, Nguyen SQ, Divino CM. Laparoscopic resection of gastric and small bowel gastrointestinal stromal tumors: 10-year experience at a single center J Am Coll Surg. 2014;218:367–73 doi: 10.1016/j.jamcollsurg.2013.11.029
24. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the jejunum and ileum: A clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up Am J Surg Pathol. 2006;30:477–89
25. Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, et al Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: A randomised, double-blind, placebo-controlled trial Lancet. 2009;373:1097–104 doi: 10.1016/S0140-6736(09)60500-6
26. DeMatteo RP, Ballman KV, Antonescu CR, Corless C, Kolesnikova V, von Mehren M, et al Long-term results of adjuvant imatinib mesylate in localized, high-risk, primary gastrointestinal stromal tumor
: ACOSOG Z9000 (Alliance) intergroup phase 2 trial Ann Surg. 2013;258:422–9 doi: 10.1097/SLA.0b013e3182a15eb7
27. Zang L, Hu WG, Yan XW, Zhang T, Ma JJ, Ye Q, et al Laparoscopic treatment for small intestinal bleeding: A report of 77 cases J Laparoendosc Adv Surg Tech A. 2010;20:521–5 doi: 10.1089/lap.2010.0022
28. Morrison JE, Hodgdon IA. Laparoscopic management of obstructing small bowel GIST tumor JSLS. 2013;17:645–50 doi: 10.4293/108680813X13X13794522667445
29. Xu X, Chen K, Zhou W, Zhang R, Wang J, Wu D, et al Laparoscopic transgastric resection of gastric submucosal tumors located near the esophagogastric junction J Gastrointest Surg. 2013;17:1570–5 doi: 10.1007/s11605-013-2241-2
Edited by: Yi Cui