- Email: [email protected]
Laparoscopic Resection of Gastric and Small Bowel Gastrointestinal Stromal Tumors: 10-Year Experience at a Single Center
Laparoscopic Resection of Gastric and Small Bowel Gastrointestinal Stromal Tumors: 10-Year Experience at a Single Center Parissa Tabrizian, MD, Robert E Sweeney, Celia M Divino, MD
MD,
Joshua H Uhr,
BA,
Scott Q Nguyen,
MD, FACS,
Complete curative resection remains the treatment of choice for nonmetastatic gastrointestinal stromal tumors (GISTs). The safety and feasibility of laparoscopy in the treatment of this disease has been shown, however, the long-term oncologic outcomes of this technique remain unclear. STUDY DESIGN: An ongoing prospectively maintained database including all laparoscopically resected gastric and small bowel GISTs (n ¼ 116) at Mount Sinai Medical Center from July 1999 to December 2011 was retrospectively analyzed. Recurrence and survival outcomes were calculated using the Kaplan-Meier method and compared with log-rank test. RESULTS: Tumors were of gastric (77.6%) and small bowel (22.4%) origins. Overall mean tumor size was 4.0 cm (2.7 cm) and R0 resection was achieved in 113 (97.4%) cases. Overall perioperative complication rate was 14.7%, with a reoperative rate of 4.3% at 90 days. When comparing gastric with small bowel GISTs, a more acute presentation requiring emergent resections was noted in patients with small bowel GISTs (p ¼ 008). However tumor size, operative data, and perioperative outcomes were comparable in both groups (p ¼ NS). At a median follow-up of 56.4 months (range 0.1 to 162.4 months), recurrence rate was 7.8% and comparable in both gastric and small bowel GISTs (p ¼ NS). Risk factors for recurrence on univariate analysis were presence of ulceration/necrosis (p < 0.001) and tumor size >5 cm (p ¼ 0.05). Overall 10-year survival rate was 90.8%. Gastric and small bowel overall survival rates were similar (90.7% vs 91.3%, respectively). Overall 10-year disease-free survival was 80.0% (84.3% gastric vs 71.6% small bowel; p ¼ NS). CONCLUSIONS: Our series demonstrates the safety and feasibility of laparoscopy in patients undergoing resection of small bowel and gastric GISTs. Comparable long-term oncologic outcomes with a 10-year survival of 90.8% were achieved. (J Am Coll Surg 2014;218:367e373. 2014 by the American College of Surgeons)
BACKGROUND:
Gastrointestinal stromal tumors (GISTs) are rare intestinal neoplasms of mesenchymal origin.1-3 Complete surgical resection with disease-free margin is considered the treatment of choice for nonmetastatic disease, with a 5-year survival rate of 40% to 55%.2,3 As demonstrated in historical series of open resections, factors associated with poor outcomes included tumor size, tumor location, mitotic index, presence of ulceration, and necrosis.4-7 Extended
tumor-free margins or lymphadenectomy have not been associated with improved oncologic outcomes.2 These unique characteristics have led many centers to investigate the feasibility and safety of a minimally invasive approach in the treatment of GISTs (Table 1).8-14 However, the long-term oncologic outcomes of this technique remain unclear. Local recurrence or distant metastasis might not be present until years after the initial diagnosis. In addition, there is paucity in the literature on the management and outcomes of laparoscopic small bowel GISTs. As a tertiary center performing a large volume of GIST resections, we present an update of our previously published results.15 The aim of this analysis was to examine our 10year experience and better understand the long-term oncologic outcomes of laparoscopic resection gastric and small bowel GISTs. In addition, we describe factors significantly associated with survival from the time of resection.
Disclosure Information: Nothing to disclose. Received September 28, 2013; Revised November 18, 2013; Accepted November 27, 2013. From the Division of General Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY. Correspondence address: Celia M Divino, MD, Division of General Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, 5 E 98th St, 15th Fl, Box 1259, New York, NY 10029. email: celia. [email protected]
ª 2014 by the American College of Surgeons Published by Elsevier Inc.
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ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.029
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Table 1.
Tabrizian et al
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Resection of Gastrointestinal Stromal Tumors
Existing Series on Laparoscopic Resection of Gastrointestinal Stromal Tumors
First author
Year
n
Small bowel, n
Tumor size, cm, mean SD (range)
Novitsky8 Lai9 Sexton10 Catena11 Karakousis12 De Vogelaere13 Pucci14
2006 2006 2008 2008 2011 2012 2012
46 28 63 21 40 31 58
0 0 0 0 0 0 0
4.4 2.0 (1.0e8.5) 3.4 1.6 3.8 1.8 (0.4e9.0) 4.5 2.0 (2.0e8.5) 3.6 (0.7e7.8) 4.4 (0.4e11) 3.8 (0.7e11.5)
Conversions, Complications, Follow-up, mo, Recurrence Survival % % % mean (range) rate, % (years)
METHODS An ongoing prospectively maintained database including all laparoscopically resected gastric and small bowel GISTs at Mount Sinai Medical Center from July 1999 to December 2011 was retrospectively analyzed. The majority of tumors (95.7%) were pathologically confirmed to be GISTs by CD117 expression. The remaining tumors were identified to have typical cytoarchitectural features of GISTs and express CD34. Records were reviewed with respect to patient demographics and outcomes, medical history, presenting symptoms, diagnostic workup, operative details, postoperative course, and pathologic characteristics. All operations were performed at our tertiary center by experienced laparoscopic surgeons. A laparoscopic to open conversion was classified as any case in which laparoscopy was used with therapeutic intent based on the operative report with subsequent creation of a laparotomy incision, regardless of the extent of attempted resection. Hand-assisted cases were classified as conversions. Mitotic rate was defined as number of mitoses per 50 high-power fields, and tumor size was defined as the maximal tumor dimension in the resected specimen. Curative resection was defined as removal of all gross disease at surgery with (R1) or without (R0) microscopic disease. The majority of cases (10) were performed at a single tertiary center by 5 different laparoscopic surgeons. The technical method used depended on tumor location, size, morphology, and surgeon’s preference. A laparoscopic or laparoendoscopic approach was used to treat all gastric lesions in our series. The patients were placed in supine position using a split-leg table in the majority of gastric cases. The operating room setup and trocar placement were similar to those of most foregut operations. The abdominal cavity was explored before resection to rule out peritoneal spread or hepatic metastasis. When in doubt, an intraoperative ultrasound was used to confirm suspicious lesions. In general, exophytic tumors were amendable to wedge resection with a linear stapling device. Tumors located on the anterior wall required a limited gastric mobilization as supposed to posterior gastric lesions. The latter were approached with an anterior
0 3.6 1.6 0 32.5 0 1.7
8.7 0 16.4 0 15 3.2 0
36 (4e84) 43.3 15 (0e103) 35 28 (0.3e70) 64.0 (1e156) d
8.0 0 4.8 0 2.5 0 d
96 (3) 100 (5) d 100 (3) d 100 (5) d
gastrotomy to allow adequate delivery of the tumor. Intraoperative endoscopy was routinely used for proximal gastric lesions to determine localization and extent of the tumor, appropriate technique for resection, as well as integrity of the staple line. An esophageal bougie was carefully positioned to assure a wide gastric inlet and its patency was confirmed with a post-resection intraoperative endoscopy. Similar to proximal tumors, distal (antral) lesions posed a technical challenge due to concern of narrowing the gastric outlet. When in doubt, a subtotal gastrectomy with Billroth II reconstruction was performed. For patients with small bowel GISTs, once the lesion Table 2. Clinicopathologic Operative Data of 116 Patients with Gastrointestinal Stromal Tumors Undergoing Resection Characteristics
Age, y, mean (SD) Sex, %, male/female Urgent/elective surgery, n (%) Tumor location, n (%) Gastric Small bowel Tumor size, cm, mean (SD) Mitotic index >5/HPF Necrosis/ulceration, n (%) CD117, n (%) Intraoperative endoscopy, n (%) R0/R1 resection, n (%) Operative time, min, mean SD (range) Estimated blood loss, mL, mean SD (range) Length of stay, d, median (range) Conversion, n (%) Perioperative 30-d morbidity, n (%) Perioperative 30-d mortality, n (%) Perioperative 90-d mortality, n (%) Reoperations, 90-d, n (%) Overall recurrence rate, n (%)
64.9 (13.7) 47.4/52.6 20 (17.2)/96 (82.8) 89 (77.6) 26 (22.4) 4.0 (2.7) 20 (17.2) 16 (13.8) 111 (95.7) 25 (21.6) 113 (97.4)/3(2.6) 134.8 67.8 (35e366) 114.3 214.3 (5e1,500) 3 (1e94) 13 (11.2) 17 (14.7) 1 (0.86) 1 (0.86) 5 (4.3) 9 (7.8)
HPF, high-power field; MI, mitotic index (number of mitotic cells per 50 high-power fields).
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Table 3.
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369
Comparative Data of Gastric (n ¼ 89) vs Small Bowel (n ¼ 26) Gastrointestinal Stromal Tumors
Characteristics
Age, y, mean SD Male sex, n (%) Symptomatic, n (%) Incidental finding, n (%) Urgent surgery, n (%) Tumor size, cm, n (%) Mitotic index >5/HPF, n (%) Necrosis/ulceration, n (%) R0/R1 resection, n (%) Length of stay, d, mean SD Conversion, n (%) Complications, n (%) Perioperative 30-d mortality, n (%) Reoperations, 90-d, n (%) Overall recurrence rate, n (%)
Gastric (n ¼ 89)
66.4 39 43 47 11 3.9 16 10 2 6.1 9 15 1 5 6
Small bowel (n ¼ 26)
(13.2) (43.8) (47.8) (52.8) (12.4) (2.9) (20) (11.2) (2.2) (13.6) (10.1) (16.7) (1.1) (5.6) (7.0)
60.4 16 17 9 9 4.2 4 6 1 3.8 4 2 0 0 3
(14.7) (61.5) (65.4) (34.6) (34.6) (2.0) (20) (23.1) (3.8) (1.6) (15.4) (7.7) (0) (0) (12.5)
p Value
0.054 0.112 0.1 0.1 0.008* 0.696 0.849 0.125 0.536 0.404 0.486 0.353 0.856 0.580 0.406
*Significant. HPF, high-power field; MI, mitotic index (number of mitotic cells per 50 high-power fields).
was identified, an extracorporeal approach was used in the majority of cases to conduct the reconstruction. Surveillance consisted of a physical examination, complete blood count, contrast-enhanced CT scan (or MRI) every 3 to 4 months for the first 2 years, every 6 months for 2 years, and then annually thereafter. Diagnosis of recurrence was generally established by radiographic means, with tissue biopsy in select circumstances. In addition to routine postoperative visits, the majority of patients were closely followed up by a gastroenterologist and an oncologist. All patients were evaluated for eligibility in a clinical trial or for adjuvant therapy. Long-term outcomes and survival were determined by the use of the Social Security Death Index and telephone interview. Overall, 93.1% of patients were successfully contacted to assess long-term outcomes. Continuous variables were presented as mean SD and compared using Student’s t-test. Categorical variables were expressed as valid percentages and compared using chi-square test or Fisher’s exact test, as appropriate. Recurrence and survival outcomes were calculated using the Kaplan-Meier method and compared with the log-rank test. Univariate analysis of multiple clinicopathologic variables (age, tumor size, mitotic index, necrosis/ulcerations, tumor site, and CD117 and CD34 expression) was performed to determine the variables associated with poor outcomes. Factors deemed significant in univariate analyses were entered into multivariate analyses using logistic and Cox regression models. A p value of <0.05 was considered significant. Statistical analysis was carried out using SPSS 20.0 software (SPSS Inc).
Institutional Review Board approval was obtained for this study.
RESULTS During the study period, a total of 116 consecutive patients underwent laparoscopic resection of GISTs. Patient characteristics are outlined in Table 2. Tumors were of gastric (77.6%) and small bowel (22.4%) origins. Asymptomatic GISTs (48.2%) were either found incidentally during the workup of other diseases or at exploration for other causes. The most common symptom (65%) necessitating emergent surgery was gastrointestinal bleeding (55.5% small bowel vs 72.7% gastric GISTs). The diagnosis of small bowel GISTs required a more extensive diagnostic workup compared with gastric GISTs. Operative and perioperative outcomes are summarized in Table 2. Overall mean tumor size was 4.0 cm (2.7 cm) and complete R0 resection was achieved in 113 (97.4%) of cases. Two patients presented with perforation. Overall conversion rate was 11.2%. Conversions in gastric (10.1%) and small bowel (15.4%) GIST resections were due to extensive adhesions, preoperative tumor perforation, tumor location (proximity to the gastroesophageal junction, duodenum), extent of disease, and/or concomitant resection of other malignant lesions. There were no incidences of iatrogenic tumor spillage or rupture and no major intraoperative complications. Overall perioperative complication rate was 14.7%, with a reoperative rate of 4.3% at 90 days. Abdominal re-explorations were due to bleeding, gastric outlet obstruction, and anastomotic leak. One
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postoperative death (0.86%) occurred in a patient undergoing a partial gastrectomy for a 7-cm GIST and hemicolectomy for colon cancer. His course was complicated by sepsis secondary to a colonic anastomotic leak. When comparing gastric with small bowel GISTs, we noted that small bowel GISTs had a more acute presentation requiring emergent resections (p ¼ 008). However, tumor size, operative data, and perioperative outcomes were comparable in both groups (p ¼ NS) (Table 3). At a median follow-up of 56.4 months (range 0.1 to 162.4 months), recurrence rate was 7.8% and comparable in both gastric and small bowel GISTs (p ¼ NS) (Fig. 1). Four patients had local recurrence and 5 patients presented with metastatic disease with no evidence of port-site recurrence. Overall 10-year recurrence rate was 12.6%. Patients with recurrent disease were treated with adjuvant therapy. Overall 10-year survival rate was 90.8% (Fig. 2). Gastric and small bowel overall survival rates were similar (90.7% vs 91.3%, respectively). Overall 10-year disease-free survival was 80.0% (84.3% gastric vs 71.6% small bowel; p ¼ NS) (Fig. 3). A subgroup survival analysis was carried out in patients (n ¼ 81) with a follow-up period of at least 3 years and outcomes were assessed. Overall 10-year recurrence and survival rates were 12.6% and 98.5%, respectively. Patient characteristics, tumor size, location, resection margin, and microscopic features (mitotic index, cellular markers, presence of necrosis or ulceration) were analyzed as prognostic factors of poor outcomes. The 5-year recurrence rate was higher in tumors >5 cm (18.7% vs 4.2%)
Figure 1. Overall recurrence rate of 116 patients with gastrointestinal stromal tumors undergoing resection.
J Am Coll Surg
(Fig. 4). Factors correlating with recurrence on univariate analysis were presence of ulceration/necrosis (p < 0.001) and tumor size >5 cm (p ¼ 0.05). Age, sex, location of tumor, resection margin, and mitotic index did not predict poor outcomes (p ¼ NS).
DISCUSSION In recent years, as the incidence of GISTs is increasing, various curative treatment methods, including the minimally invasive approach, have been proposed.8-14 Although there are no prospective randomized trials comparing open with laparoscopic approaches, several retrospective studies demonstrated comparable results with the latter technique (Table 1).8-14 However, the long-term oncologic outcomes of this procedure are not well established. We report the largest series of 116 patients with gastric and small bowel GISTs treated with laparoscopic resection at a single center. Our series demonstrates that resection of GISTs is feasible and can be safely accomplished with the laparoscopic technique. The conversion rate demonstrated in our study (11.2%) was higher than rates published in other series. This can be explained by small tumor size or patient selection in other series, as well as the criteria used to define conversion in this study. Factors associated with failure of the minimally invasive approach were extensive adhesions, preoperative tumor perforation, proximity to the gastroesophageal junction or proximal small bowel, extent of disease, and/or concomitant
Figure 2. Overall survival rate of 116 patients with gastrointestinal stromal tumors undergoing resection (p ¼ NS).
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Figure 3. Disease-free survival of gastric (n ¼ 89) versus small bowel (n ¼ 26) Gastrointestinal Stromal Tumors (p ¼ NS).
resection of other malignant lesions. These factors are critical and should help in selecting the patients preoperatively. Tumor location and size appear to be important variables determining the surgical approach. According to the modified National Comprehensive Cancer Network guidelines, tumors up to 5 cm can be safely approached laparoscopically.16,17 As long as all oncologic principles were met, tumor size alone was not a contraindication to a laparoscopic approach in our series. Tumors up to 11.5 cm were removed successfully in our study. According to the literature, complication rates for patients who underwent laparoscopic resection of GISTs range from 0% to 16.7%.8-14 We demonstrate acceptable rates of morbidity (14.7%) and mortality (0.86%) in patients undergoing resection of GIST tumors in our study. The majority of complications in this group were managed conservatively. Our series demonstrates acceptable long-term outcomes of laparoscopic excision of GISTs. Large retrospective studies published by Miettinen and colleagues reviewing 1,765 specimens demonstrated a disease-free survival rate of 48%.3 We report a 10-year overall survival rate and disease-free survival rate of 90.8% and 81.3%, respectively. Comparison can be difficult, as these large studies were performed before the era of adjuvant/neoadjuvant therapy, including non-GISTs tumors, larger tumor size achieving decreased R0 resection.18 These factors might have contributed to lower survival rate. In addition, many studies included recurrent and metastatic tumors in their survival analysis. To date, outcomes similar to
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Figure 4. Overall recurrence rate of 116 patients with gastrointestinal stromal tumors undergoing resection stratified according to tumor size (p ¼ 0.05).
our experience have been published in the laparoscopic group (Table 1).8-14 In our series, standard oncologic principles were not sacrificed. We had no evidence of tumor spillage or rupture and achieved an R0 resection in 97.4% of cases. Inability to adhere to these principles mandated conversion to an open technique. In addition, we did not identify any port-site recurrences. Only a few small studies have compared both techniques. Karakousis and colleagues reported similar oncologic outcomes in a size-matched analysis of laparoscopic vs open cases.12,19 Reports of long-term results after laparoscopic resection of tumors >5 cm remain rare. Patient selection bias might have contributed to such high success rates in previous published data. The patients in our series were selected based on a variety of factors, such as patient characteristics, tumor size, invasion, location, and whether procedure is performed by a laparoscopic surgeon. Based on several large retrospective analyses, meaningful prognostic characteristics of surgically treated GISTs have been identified.2-4 Factors associated with poor outcomes in our series were size >5 cm and presence of necrosis/ulceration. Microscopic margin (R1) and high mitotic index did not predict poor outcomes in our analysis. However, these findings need to be validated by a larger sample size. Novitsky and colleagues identified tumor size and high mitotic index (>10/50 high-power fields) as significant predictors of recurrence.8 Tumor mitotic rate was also described as a risk factor in large
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open series.5 The importance of microscopic surgical margin, however, remains controversial in the management of GIST. Because it failed to influence outcomes, Dematteo and colleagues suggested that R1 resection might not be a critical factor.2 No difference in outcomes was also suggested in a recent meta-analysis.20 None of the patients in our series were treated with neoadjuvant therapy. All patients with recurrent or metastatic disease were treated with adjuvant therapy. Of the 28 patients with large tumor size (>5 cm), only 4 died of disease at follow-up of 0.5, 7, 26, and 30 months respectively. Lastly, there is a paucity of literature on the safety and outcomes of laparoscopic resection of small bowel GISTs. The majority of large open series of small bowel GISTs were conducted before the era of neoadjuvant/ adjuvant therapy and the precise tumor biology is unclear.21,22 These investigators reported 5-year survival rates ranging from 41% to 50.5%.21-23 With 26 small bowel cases, we report the largest published series treated using the minimally invasive approach. Small bowel GISTs were incidentally found during the workup of other diseases in up to one third of our patients. Overall, the diagnostic workup was more extensive compared with gastric GISTs. The only significant variable we identified in both groups was the need for increased emergent resection in patients diagnosed with small bowel GISTs secondary to hemorrhage, obstruction, or perforation. The conversion rate of 7.7% due to proximal tumor location (duodenum), extensive adhesions, and preoperative tumor perforation was comparable with that of other laparoscopic GIST series. Complications in this group were all managed conservatively with no perioperative mortality. There is also considerable evidence in the literature that anatomic site has a prognostic implication, with small bowel GISTs having a worse prognosis than gastric lesions.21-23 Compared with gastric tumors, small bowel tumors with similar size and mitotic index had a markedly worse prognosis in a large series with decreased recurrence-free survival rate.21 Our series failed to show any statistically significant factor associated with poor outcomes and tumor site. Patients with small bowel GISTs had a higher recurrence rate (21.6% vs 8%) and lower disease-free survival rate (71.6% vs 84.3%). However, the outcomes were comparable in both groups (p ¼ NS). These findings need to be investigated in a future larger series. The influence of anatomic location is unclear and has been debated in the literature. Immunohistochemical and genetic differences between GISTs from various anatomic sites could explain the difference in tumor behavior. Our data support the minimally invasive approach for the treatment of small bowel GISTs.
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CONCLUSIONS Complete resection remains the treatment of choice in the management of GISTs. Their unique biologic behavior has expanded the use of a minimally invasive approach in the resection of these tumors. Our series demonstrates the safe alternative of laparoscopic resection of GISTs compared with open resection, with comparable operative and long-term oncologic outcomes and a 10-year survival rate of 90.8%. Author Contributions Study conception and design: Tabrizian, Nguyen, Divino Acquisition of data: Tabrizian, Sweeney, Uhr Analysis and interpretation of data: Tabrizian, Nguyen, Divino Drafting of manuscript: Tabrizian, Nguyen, Divino Critical revision: Tabrizian, Divino REFERENCES 1. Hirota S, Isozaki K, Moriyama Y, et al. Gain of function mutations of c-kit in humangastrointestinal stromal tumors. Science 1998;279:577e580. 2. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51e58. 3. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005;29:52e68. 4. Joensuu H, Fletcher C, Dimitrijevic S, et al. Management of malignant gastrointestinal stromal tumours. Lancet Oncol 2002;3:664. 5. Dematteo RP, Gold JS, Saran L, et al. Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008;112:608e615. 6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006;23:70e83. 7. Hassan I, You YN, Shyyan R, et al. Surgically managed gastrointestinal stromal tumors: a comparative and prognostic analysis. Ann Surg Oncol 2008;15:52e59. 8. Novitsky YW, Kercher KW, Sing RF, Heniford BT. Longterm outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg 2006;243:738e745; discussion 745747. 9. Lai IR, Lee WJ, Yu SC. Minimally invasive surgery for gastric stromal cell tumors: intermediate follow-up results. J Gastrointest Surg 2006;10:563e566. 10. Sexton JA, Pierce RA, Halpin VJ, et al. Laparoscopic gastric resection for gastrointestinal stromal tumors. Surg Endosc 2008;22:2583. 11. Catena F, Di Battista M, Fusaroli P, et al. Laparoscopic treatment of gastric GIST: report of 21 cases and literature’s review. J Gastrointest Surg 2008;12:561e568. 12. Karakousis GC, Singer S, Zheng J, et al. Laparoscopic versus open gastric resections for primary gastrointestinal stromal
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13.
14. 15. 16.
17.
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tumors (GISTs): a size-matched comparison. Ann Surg Oncol 2011;18:1599e1605. De Vogelaere K, Van Loo I, Peters O, et al. Laparoscopic resection of gastric gastrointestinal stromal tumors (GIST) is safe and effective, irrespective of tumor size. Surg Endosc 2012;26:2339e2345. Pucci MJ, Berger AC, Lim PW, et al. Laparoscopic approaches to gastric gastrointestinal stromal tumors: an institutional review of 57 cases. Surg Endosc 2012;26:3509e3510. Tabrizian P, Nguyen SQ, Divino CM. Laparoscopic management and long-term outcomes of gastrointestinal stromal tumors. J Am Coll Surg 2009;208:80e86. Demetri GD, Benjamin R, Blanke CD. NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)dexpansion and update of NCCN. clinical practice guidelines. J Natl Compr Canc Netw 2004;2[Suppl 1]:S-1eS-26. quiz 2730. Demetri GD, Benjamin RS, Blanke CD. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)dupdate of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2007;5[Suppl 2]:S1eS29; quiz S30. Review. Erratum in: J Natl Compr Canc Netw. 2007;5:xxx.
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18. Dematteo RP, Ballman KV, Antonescu CR. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebocontrolled trial. Lancet 2009;373:1097e1104. 19. Matthews BD, Walsh RM, Kercher KW, et al. Laparoscopic vs open resection of gastric stromal tumors. Surg Endosc 2002; 16:803e807. 20. Koh YX, Chok AY, Zheng HL, et al. A systematic review and meta analysis comparing laparoscopic versus open gastric resections for gastrointestinal stromal tumors of the stomach. Ann Surg Oncol 2013;20:3549e3560. 21. Miettinen M, Makhlouf H, Sobin LH, et al. 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;30:477e489. 22. Emory TS, Sobin LH, Lukes L, et al. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. Am J Surg Pathol 1999;23:82e87. 23. Crosby JA, Catton CN, Davis A, et al. Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann Surg Oncol 2001;8:50e59.
MD,
Joshua H Uhr,
BA,
Scott Q Nguyen,
MD, FACS,
Complete curative resection remains the treatment of choice for nonmetastatic gastrointestinal stromal tumors (GISTs). The safety and feasibility of laparoscopy in the treatment of this disease has been shown, however, the long-term oncologic outcomes of this technique remain unclear. STUDY DESIGN: An ongoing prospectively maintained database including all laparoscopically resected gastric and small bowel GISTs (n ¼ 116) at Mount Sinai Medical Center from July 1999 to December 2011 was retrospectively analyzed. Recurrence and survival outcomes were calculated using the Kaplan-Meier method and compared with log-rank test. RESULTS: Tumors were of gastric (77.6%) and small bowel (22.4%) origins. Overall mean tumor size was 4.0 cm (2.7 cm) and R0 resection was achieved in 113 (97.4%) cases. Overall perioperative complication rate was 14.7%, with a reoperative rate of 4.3% at 90 days. When comparing gastric with small bowel GISTs, a more acute presentation requiring emergent resections was noted in patients with small bowel GISTs (p ¼ 008). However tumor size, operative data, and perioperative outcomes were comparable in both groups (p ¼ NS). At a median follow-up of 56.4 months (range 0.1 to 162.4 months), recurrence rate was 7.8% and comparable in both gastric and small bowel GISTs (p ¼ NS). Risk factors for recurrence on univariate analysis were presence of ulceration/necrosis (p < 0.001) and tumor size >5 cm (p ¼ 0.05). Overall 10-year survival rate was 90.8%. Gastric and small bowel overall survival rates were similar (90.7% vs 91.3%, respectively). Overall 10-year disease-free survival was 80.0% (84.3% gastric vs 71.6% small bowel; p ¼ NS). CONCLUSIONS: Our series demonstrates the safety and feasibility of laparoscopy in patients undergoing resection of small bowel and gastric GISTs. Comparable long-term oncologic outcomes with a 10-year survival of 90.8% were achieved. (J Am Coll Surg 2014;218:367e373. 2014 by the American College of Surgeons)
BACKGROUND:
Gastrointestinal stromal tumors (GISTs) are rare intestinal neoplasms of mesenchymal origin.1-3 Complete surgical resection with disease-free margin is considered the treatment of choice for nonmetastatic disease, with a 5-year survival rate of 40% to 55%.2,3 As demonstrated in historical series of open resections, factors associated with poor outcomes included tumor size, tumor location, mitotic index, presence of ulceration, and necrosis.4-7 Extended
tumor-free margins or lymphadenectomy have not been associated with improved oncologic outcomes.2 These unique characteristics have led many centers to investigate the feasibility and safety of a minimally invasive approach in the treatment of GISTs (Table 1).8-14 However, the long-term oncologic outcomes of this technique remain unclear. Local recurrence or distant metastasis might not be present until years after the initial diagnosis. In addition, there is paucity in the literature on the management and outcomes of laparoscopic small bowel GISTs. As a tertiary center performing a large volume of GIST resections, we present an update of our previously published results.15 The aim of this analysis was to examine our 10year experience and better understand the long-term oncologic outcomes of laparoscopic resection gastric and small bowel GISTs. In addition, we describe factors significantly associated with survival from the time of resection.
Disclosure Information: Nothing to disclose. Received September 28, 2013; Revised November 18, 2013; Accepted November 27, 2013. From the Division of General Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY. Correspondence address: Celia M Divino, MD, Division of General Surgery, Department of Surgery, Icahn School of Medicine at Mount Sinai, 5 E 98th St, 15th Fl, Box 1259, New York, NY 10029. email: celia. [email protected]
ª 2014 by the American College of Surgeons Published by Elsevier Inc.
367
ISSN 1072-7515/13/$36.00 http://dx.doi.org/10.1016/j.jamcollsurg.2013.11.029
368
Table 1.
Tabrizian et al
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Resection of Gastrointestinal Stromal Tumors
Existing Series on Laparoscopic Resection of Gastrointestinal Stromal Tumors
First author
Year
n
Small bowel, n
Tumor size, cm, mean SD (range)
Novitsky8 Lai9 Sexton10 Catena11 Karakousis12 De Vogelaere13 Pucci14
2006 2006 2008 2008 2011 2012 2012
46 28 63 21 40 31 58
0 0 0 0 0 0 0
4.4 2.0 (1.0e8.5) 3.4 1.6 3.8 1.8 (0.4e9.0) 4.5 2.0 (2.0e8.5) 3.6 (0.7e7.8) 4.4 (0.4e11) 3.8 (0.7e11.5)
Conversions, Complications, Follow-up, mo, Recurrence Survival % % % mean (range) rate, % (years)
METHODS An ongoing prospectively maintained database including all laparoscopically resected gastric and small bowel GISTs at Mount Sinai Medical Center from July 1999 to December 2011 was retrospectively analyzed. The majority of tumors (95.7%) were pathologically confirmed to be GISTs by CD117 expression. The remaining tumors were identified to have typical cytoarchitectural features of GISTs and express CD34. Records were reviewed with respect to patient demographics and outcomes, medical history, presenting symptoms, diagnostic workup, operative details, postoperative course, and pathologic characteristics. All operations were performed at our tertiary center by experienced laparoscopic surgeons. A laparoscopic to open conversion was classified as any case in which laparoscopy was used with therapeutic intent based on the operative report with subsequent creation of a laparotomy incision, regardless of the extent of attempted resection. Hand-assisted cases were classified as conversions. Mitotic rate was defined as number of mitoses per 50 high-power fields, and tumor size was defined as the maximal tumor dimension in the resected specimen. Curative resection was defined as removal of all gross disease at surgery with (R1) or without (R0) microscopic disease. The majority of cases (10) were performed at a single tertiary center by 5 different laparoscopic surgeons. The technical method used depended on tumor location, size, morphology, and surgeon’s preference. A laparoscopic or laparoendoscopic approach was used to treat all gastric lesions in our series. The patients were placed in supine position using a split-leg table in the majority of gastric cases. The operating room setup and trocar placement were similar to those of most foregut operations. The abdominal cavity was explored before resection to rule out peritoneal spread or hepatic metastasis. When in doubt, an intraoperative ultrasound was used to confirm suspicious lesions. In general, exophytic tumors were amendable to wedge resection with a linear stapling device. Tumors located on the anterior wall required a limited gastric mobilization as supposed to posterior gastric lesions. The latter were approached with an anterior
0 3.6 1.6 0 32.5 0 1.7
8.7 0 16.4 0 15 3.2 0
36 (4e84) 43.3 15 (0e103) 35 28 (0.3e70) 64.0 (1e156) d
8.0 0 4.8 0 2.5 0 d
96 (3) 100 (5) d 100 (3) d 100 (5) d
gastrotomy to allow adequate delivery of the tumor. Intraoperative endoscopy was routinely used for proximal gastric lesions to determine localization and extent of the tumor, appropriate technique for resection, as well as integrity of the staple line. An esophageal bougie was carefully positioned to assure a wide gastric inlet and its patency was confirmed with a post-resection intraoperative endoscopy. Similar to proximal tumors, distal (antral) lesions posed a technical challenge due to concern of narrowing the gastric outlet. When in doubt, a subtotal gastrectomy with Billroth II reconstruction was performed. For patients with small bowel GISTs, once the lesion Table 2. Clinicopathologic Operative Data of 116 Patients with Gastrointestinal Stromal Tumors Undergoing Resection Characteristics
Age, y, mean (SD) Sex, %, male/female Urgent/elective surgery, n (%) Tumor location, n (%) Gastric Small bowel Tumor size, cm, mean (SD) Mitotic index >5/HPF Necrosis/ulceration, n (%) CD117, n (%) Intraoperative endoscopy, n (%) R0/R1 resection, n (%) Operative time, min, mean SD (range) Estimated blood loss, mL, mean SD (range) Length of stay, d, median (range) Conversion, n (%) Perioperative 30-d morbidity, n (%) Perioperative 30-d mortality, n (%) Perioperative 90-d mortality, n (%) Reoperations, 90-d, n (%) Overall recurrence rate, n (%)
64.9 (13.7) 47.4/52.6 20 (17.2)/96 (82.8) 89 (77.6) 26 (22.4) 4.0 (2.7) 20 (17.2) 16 (13.8) 111 (95.7) 25 (21.6) 113 (97.4)/3(2.6) 134.8 67.8 (35e366) 114.3 214.3 (5e1,500) 3 (1e94) 13 (11.2) 17 (14.7) 1 (0.86) 1 (0.86) 5 (4.3) 9 (7.8)
HPF, high-power field; MI, mitotic index (number of mitotic cells per 50 high-power fields).
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Table 3.
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Comparative Data of Gastric (n ¼ 89) vs Small Bowel (n ¼ 26) Gastrointestinal Stromal Tumors
Characteristics
Age, y, mean SD Male sex, n (%) Symptomatic, n (%) Incidental finding, n (%) Urgent surgery, n (%) Tumor size, cm, n (%) Mitotic index >5/HPF, n (%) Necrosis/ulceration, n (%) R0/R1 resection, n (%) Length of stay, d, mean SD Conversion, n (%) Complications, n (%) Perioperative 30-d mortality, n (%) Reoperations, 90-d, n (%) Overall recurrence rate, n (%)
Gastric (n ¼ 89)
66.4 39 43 47 11 3.9 16 10 2 6.1 9 15 1 5 6
Small bowel (n ¼ 26)
(13.2) (43.8) (47.8) (52.8) (12.4) (2.9) (20) (11.2) (2.2) (13.6) (10.1) (16.7) (1.1) (5.6) (7.0)
60.4 16 17 9 9 4.2 4 6 1 3.8 4 2 0 0 3
(14.7) (61.5) (65.4) (34.6) (34.6) (2.0) (20) (23.1) (3.8) (1.6) (15.4) (7.7) (0) (0) (12.5)
p Value
0.054 0.112 0.1 0.1 0.008* 0.696 0.849 0.125 0.536 0.404 0.486 0.353 0.856 0.580 0.406
*Significant. HPF, high-power field; MI, mitotic index (number of mitotic cells per 50 high-power fields).
was identified, an extracorporeal approach was used in the majority of cases to conduct the reconstruction. Surveillance consisted of a physical examination, complete blood count, contrast-enhanced CT scan (or MRI) every 3 to 4 months for the first 2 years, every 6 months for 2 years, and then annually thereafter. Diagnosis of recurrence was generally established by radiographic means, with tissue biopsy in select circumstances. In addition to routine postoperative visits, the majority of patients were closely followed up by a gastroenterologist and an oncologist. All patients were evaluated for eligibility in a clinical trial or for adjuvant therapy. Long-term outcomes and survival were determined by the use of the Social Security Death Index and telephone interview. Overall, 93.1% of patients were successfully contacted to assess long-term outcomes. Continuous variables were presented as mean SD and compared using Student’s t-test. Categorical variables were expressed as valid percentages and compared using chi-square test or Fisher’s exact test, as appropriate. Recurrence and survival outcomes were calculated using the Kaplan-Meier method and compared with the log-rank test. Univariate analysis of multiple clinicopathologic variables (age, tumor size, mitotic index, necrosis/ulcerations, tumor site, and CD117 and CD34 expression) was performed to determine the variables associated with poor outcomes. Factors deemed significant in univariate analyses were entered into multivariate analyses using logistic and Cox regression models. A p value of <0.05 was considered significant. Statistical analysis was carried out using SPSS 20.0 software (SPSS Inc).
Institutional Review Board approval was obtained for this study.
RESULTS During the study period, a total of 116 consecutive patients underwent laparoscopic resection of GISTs. Patient characteristics are outlined in Table 2. Tumors were of gastric (77.6%) and small bowel (22.4%) origins. Asymptomatic GISTs (48.2%) were either found incidentally during the workup of other diseases or at exploration for other causes. The most common symptom (65%) necessitating emergent surgery was gastrointestinal bleeding (55.5% small bowel vs 72.7% gastric GISTs). The diagnosis of small bowel GISTs required a more extensive diagnostic workup compared with gastric GISTs. Operative and perioperative outcomes are summarized in Table 2. Overall mean tumor size was 4.0 cm (2.7 cm) and complete R0 resection was achieved in 113 (97.4%) of cases. Two patients presented with perforation. Overall conversion rate was 11.2%. Conversions in gastric (10.1%) and small bowel (15.4%) GIST resections were due to extensive adhesions, preoperative tumor perforation, tumor location (proximity to the gastroesophageal junction, duodenum), extent of disease, and/or concomitant resection of other malignant lesions. There were no incidences of iatrogenic tumor spillage or rupture and no major intraoperative complications. Overall perioperative complication rate was 14.7%, with a reoperative rate of 4.3% at 90 days. Abdominal re-explorations were due to bleeding, gastric outlet obstruction, and anastomotic leak. One
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postoperative death (0.86%) occurred in a patient undergoing a partial gastrectomy for a 7-cm GIST and hemicolectomy for colon cancer. His course was complicated by sepsis secondary to a colonic anastomotic leak. When comparing gastric with small bowel GISTs, we noted that small bowel GISTs had a more acute presentation requiring emergent resections (p ¼ 008). However, tumor size, operative data, and perioperative outcomes were comparable in both groups (p ¼ NS) (Table 3). At a median follow-up of 56.4 months (range 0.1 to 162.4 months), recurrence rate was 7.8% and comparable in both gastric and small bowel GISTs (p ¼ NS) (Fig. 1). Four patients had local recurrence and 5 patients presented with metastatic disease with no evidence of port-site recurrence. Overall 10-year recurrence rate was 12.6%. Patients with recurrent disease were treated with adjuvant therapy. Overall 10-year survival rate was 90.8% (Fig. 2). Gastric and small bowel overall survival rates were similar (90.7% vs 91.3%, respectively). Overall 10-year disease-free survival was 80.0% (84.3% gastric vs 71.6% small bowel; p ¼ NS) (Fig. 3). A subgroup survival analysis was carried out in patients (n ¼ 81) with a follow-up period of at least 3 years and outcomes were assessed. Overall 10-year recurrence and survival rates were 12.6% and 98.5%, respectively. Patient characteristics, tumor size, location, resection margin, and microscopic features (mitotic index, cellular markers, presence of necrosis or ulceration) were analyzed as prognostic factors of poor outcomes. The 5-year recurrence rate was higher in tumors >5 cm (18.7% vs 4.2%)
Figure 1. Overall recurrence rate of 116 patients with gastrointestinal stromal tumors undergoing resection.
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(Fig. 4). Factors correlating with recurrence on univariate analysis were presence of ulceration/necrosis (p < 0.001) and tumor size >5 cm (p ¼ 0.05). Age, sex, location of tumor, resection margin, and mitotic index did not predict poor outcomes (p ¼ NS).
DISCUSSION In recent years, as the incidence of GISTs is increasing, various curative treatment methods, including the minimally invasive approach, have been proposed.8-14 Although there are no prospective randomized trials comparing open with laparoscopic approaches, several retrospective studies demonstrated comparable results with the latter technique (Table 1).8-14 However, the long-term oncologic outcomes of this procedure are not well established. We report the largest series of 116 patients with gastric and small bowel GISTs treated with laparoscopic resection at a single center. Our series demonstrates that resection of GISTs is feasible and can be safely accomplished with the laparoscopic technique. The conversion rate demonstrated in our study (11.2%) was higher than rates published in other series. This can be explained by small tumor size or patient selection in other series, as well as the criteria used to define conversion in this study. Factors associated with failure of the minimally invasive approach were extensive adhesions, preoperative tumor perforation, proximity to the gastroesophageal junction or proximal small bowel, extent of disease, and/or concomitant
Figure 2. Overall survival rate of 116 patients with gastrointestinal stromal tumors undergoing resection (p ¼ NS).
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Figure 3. Disease-free survival of gastric (n ¼ 89) versus small bowel (n ¼ 26) Gastrointestinal Stromal Tumors (p ¼ NS).
resection of other malignant lesions. These factors are critical and should help in selecting the patients preoperatively. Tumor location and size appear to be important variables determining the surgical approach. According to the modified National Comprehensive Cancer Network guidelines, tumors up to 5 cm can be safely approached laparoscopically.16,17 As long as all oncologic principles were met, tumor size alone was not a contraindication to a laparoscopic approach in our series. Tumors up to 11.5 cm were removed successfully in our study. According to the literature, complication rates for patients who underwent laparoscopic resection of GISTs range from 0% to 16.7%.8-14 We demonstrate acceptable rates of morbidity (14.7%) and mortality (0.86%) in patients undergoing resection of GIST tumors in our study. The majority of complications in this group were managed conservatively. Our series demonstrates acceptable long-term outcomes of laparoscopic excision of GISTs. Large retrospective studies published by Miettinen and colleagues reviewing 1,765 specimens demonstrated a disease-free survival rate of 48%.3 We report a 10-year overall survival rate and disease-free survival rate of 90.8% and 81.3%, respectively. Comparison can be difficult, as these large studies were performed before the era of adjuvant/neoadjuvant therapy, including non-GISTs tumors, larger tumor size achieving decreased R0 resection.18 These factors might have contributed to lower survival rate. In addition, many studies included recurrent and metastatic tumors in their survival analysis. To date, outcomes similar to
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Figure 4. Overall recurrence rate of 116 patients with gastrointestinal stromal tumors undergoing resection stratified according to tumor size (p ¼ 0.05).
our experience have been published in the laparoscopic group (Table 1).8-14 In our series, standard oncologic principles were not sacrificed. We had no evidence of tumor spillage or rupture and achieved an R0 resection in 97.4% of cases. Inability to adhere to these principles mandated conversion to an open technique. In addition, we did not identify any port-site recurrences. Only a few small studies have compared both techniques. Karakousis and colleagues reported similar oncologic outcomes in a size-matched analysis of laparoscopic vs open cases.12,19 Reports of long-term results after laparoscopic resection of tumors >5 cm remain rare. Patient selection bias might have contributed to such high success rates in previous published data. The patients in our series were selected based on a variety of factors, such as patient characteristics, tumor size, invasion, location, and whether procedure is performed by a laparoscopic surgeon. Based on several large retrospective analyses, meaningful prognostic characteristics of surgically treated GISTs have been identified.2-4 Factors associated with poor outcomes in our series were size >5 cm and presence of necrosis/ulceration. Microscopic margin (R1) and high mitotic index did not predict poor outcomes in our analysis. However, these findings need to be validated by a larger sample size. Novitsky and colleagues identified tumor size and high mitotic index (>10/50 high-power fields) as significant predictors of recurrence.8 Tumor mitotic rate was also described as a risk factor in large
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open series.5 The importance of microscopic surgical margin, however, remains controversial in the management of GIST. Because it failed to influence outcomes, Dematteo and colleagues suggested that R1 resection might not be a critical factor.2 No difference in outcomes was also suggested in a recent meta-analysis.20 None of the patients in our series were treated with neoadjuvant therapy. All patients with recurrent or metastatic disease were treated with adjuvant therapy. Of the 28 patients with large tumor size (>5 cm), only 4 died of disease at follow-up of 0.5, 7, 26, and 30 months respectively. Lastly, there is a paucity of literature on the safety and outcomes of laparoscopic resection of small bowel GISTs. The majority of large open series of small bowel GISTs were conducted before the era of neoadjuvant/ adjuvant therapy and the precise tumor biology is unclear.21,22 These investigators reported 5-year survival rates ranging from 41% to 50.5%.21-23 With 26 small bowel cases, we report the largest published series treated using the minimally invasive approach. Small bowel GISTs were incidentally found during the workup of other diseases in up to one third of our patients. Overall, the diagnostic workup was more extensive compared with gastric GISTs. The only significant variable we identified in both groups was the need for increased emergent resection in patients diagnosed with small bowel GISTs secondary to hemorrhage, obstruction, or perforation. The conversion rate of 7.7% due to proximal tumor location (duodenum), extensive adhesions, and preoperative tumor perforation was comparable with that of other laparoscopic GIST series. Complications in this group were all managed conservatively with no perioperative mortality. There is also considerable evidence in the literature that anatomic site has a prognostic implication, with small bowel GISTs having a worse prognosis than gastric lesions.21-23 Compared with gastric tumors, small bowel tumors with similar size and mitotic index had a markedly worse prognosis in a large series with decreased recurrence-free survival rate.21 Our series failed to show any statistically significant factor associated with poor outcomes and tumor site. Patients with small bowel GISTs had a higher recurrence rate (21.6% vs 8%) and lower disease-free survival rate (71.6% vs 84.3%). However, the outcomes were comparable in both groups (p ¼ NS). These findings need to be investigated in a future larger series. The influence of anatomic location is unclear and has been debated in the literature. Immunohistochemical and genetic differences between GISTs from various anatomic sites could explain the difference in tumor behavior. Our data support the minimally invasive approach for the treatment of small bowel GISTs.
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CONCLUSIONS Complete resection remains the treatment of choice in the management of GISTs. Their unique biologic behavior has expanded the use of a minimally invasive approach in the resection of these tumors. Our series demonstrates the safe alternative of laparoscopic resection of GISTs compared with open resection, with comparable operative and long-term oncologic outcomes and a 10-year survival rate of 90.8%. Author Contributions Study conception and design: Tabrizian, Nguyen, Divino Acquisition of data: Tabrizian, Sweeney, Uhr Analysis and interpretation of data: Tabrizian, Nguyen, Divino Drafting of manuscript: Tabrizian, Nguyen, Divino Critical revision: Tabrizian, Divino REFERENCES 1. Hirota S, Isozaki K, Moriyama Y, et al. Gain of function mutations of c-kit in humangastrointestinal stromal tumors. Science 1998;279:577e580. 2. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51e58. 3. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005;29:52e68. 4. Joensuu H, Fletcher C, Dimitrijevic S, et al. Management of malignant gastrointestinal stromal tumours. Lancet Oncol 2002;3:664. 5. Dematteo RP, Gold JS, Saran L, et al. Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008;112:608e615. 6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006;23:70e83. 7. Hassan I, You YN, Shyyan R, et al. Surgically managed gastrointestinal stromal tumors: a comparative and prognostic analysis. Ann Surg Oncol 2008;15:52e59. 8. Novitsky YW, Kercher KW, Sing RF, Heniford BT. Longterm outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg 2006;243:738e745; discussion 745747. 9. Lai IR, Lee WJ, Yu SC. Minimally invasive surgery for gastric stromal cell tumors: intermediate follow-up results. J Gastrointest Surg 2006;10:563e566. 10. Sexton JA, Pierce RA, Halpin VJ, et al. Laparoscopic gastric resection for gastrointestinal stromal tumors. Surg Endosc 2008;22:2583. 11. Catena F, Di Battista M, Fusaroli P, et al. Laparoscopic treatment of gastric GIST: report of 21 cases and literature’s review. J Gastrointest Surg 2008;12:561e568. 12. Karakousis GC, Singer S, Zheng J, et al. Laparoscopic versus open gastric resections for primary gastrointestinal stromal
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tumors (GISTs): a size-matched comparison. Ann Surg Oncol 2011;18:1599e1605. De Vogelaere K, Van Loo I, Peters O, et al. Laparoscopic resection of gastric gastrointestinal stromal tumors (GIST) is safe and effective, irrespective of tumor size. Surg Endosc 2012;26:2339e2345. Pucci MJ, Berger AC, Lim PW, et al. Laparoscopic approaches to gastric gastrointestinal stromal tumors: an institutional review of 57 cases. Surg Endosc 2012;26:3509e3510. Tabrizian P, Nguyen SQ, Divino CM. Laparoscopic management and long-term outcomes of gastrointestinal stromal tumors. J Am Coll Surg 2009;208:80e86. Demetri GD, Benjamin R, Blanke CD. NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)dexpansion and update of NCCN. clinical practice guidelines. J Natl Compr Canc Netw 2004;2[Suppl 1]:S-1eS-26. quiz 2730. Demetri GD, Benjamin RS, Blanke CD. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)dupdate of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2007;5[Suppl 2]:S1eS29; quiz S30. Review. Erratum in: J Natl Compr Canc Netw. 2007;5:xxx.
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18. Dematteo RP, Ballman KV, Antonescu CR. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebocontrolled trial. Lancet 2009;373:1097e1104. 19. Matthews BD, Walsh RM, Kercher KW, et al. Laparoscopic vs open resection of gastric stromal tumors. Surg Endosc 2002; 16:803e807. 20. Koh YX, Chok AY, Zheng HL, et al. A systematic review and meta analysis comparing laparoscopic versus open gastric resections for gastrointestinal stromal tumors of the stomach. Ann Surg Oncol 2013;20:3549e3560. 21. Miettinen M, Makhlouf H, Sobin LH, et al. 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;30:477e489. 22. Emory TS, Sobin LH, Lukes L, et al. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. Am J Surg Pathol 1999;23:82e87. 23. Crosby JA, Catton CN, Davis A, et al. Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann Surg Oncol 2001;8:50e59.