Laparoscopic Resection of Gastrointestinal Stromal Tumors: Safe,Efficient,and Comparable Oncologic Outcomes

Abstract

Background:

Surgery of gastrointestinal stromal tumors (GISTs) has been modified, and laparoscopic resection of GIST has gained improvement and roles.

Patients and Methods:

We retrospectively reviewed clinical data and oncological outcomes of our GIST patients who underwent laparoscopic surgery and traditional open surgery. In total, 227 pathologically diagnosed GIST cases were retrospectively reviewed in Chang Gung Memorial Hospital at Linkou, Taipei, Taiwan, between 2005 and 2010. We excluded those with tumor size >5 cm, biopsy-only, combined other operation, endoscopic mucosal resection, tumor located in the duodenum, colon–rectum, esophagocardiac junction, omentum, pelvic area, or retroperitoneum, or metastasis when operated on and those diagnosed as other disease after immunohistologic examination of GIST. Fifty-eight cases were enrolled, including 16 patients in the laparoscopic surgery group (LSG) and 42 patients in the open surgery group (OSG). The patients' demography, perioperative, pathologic result, and oncology result were recorded and analyzed.

Results:

Both groups showed no difference in clinical demography, tumor size, and locations. LSG patients showed fewer days to resume diet, shorter postoperative hospital stays, and less use of patient-controlled analgesia. The postoperative morbidity in LSG and OSG was 6.3% and 19%, respectively. The median follow-up time was 32.73 months in LSG and 39.75 months in OSG. Recurrence or metastasis was observed in 3 patients (1 in LSG and 2 in OSG). The recurrence rate between LSG and OSG showed no significant difference.

Conclusions:

Laparoscopic surgery was technically feasible for GIST of no more than 5 cm located at the stomach and small bowel. In the current study, we demonstrated that LSG patients benefited from fewer days to resume diet (5 versus 5.71 days), shorter postoperative stays (8 versus 9.07 days), and less patient-controlled analgesia use (6.7% versus 90.9%) during the perioperative period with the same short-term oncology result compared with OSG patients.

Background

Gastrointestinal (GI) stromal tumors (GISTs) are rare neoplasms and represent approximately 0.1%–3% of all GI tumors. The stomach is the site of origin for more than 50% of these tumors, and the small bowel for around 30%.¹ The annual incidence rate is 13.74 per million in Taiwan.² GISTs are known to originate from GI pacemaker cells, named the interstitial cells of Cajal. Mutations in the c-kit proto-oncogene and overexpression of the KIT protein result in tumor growth.^3,4 Because the KIT tyrosine kinase inhibitor imatinib mesylate (Gleevec^®, formerly known as ST1571; Novartis Pharm AG, Basel, Switzerland) showed promising clinical results in advanced GIST patients, KIT-immunopositivity is important for the diagnosis and treatment of GISTs.⁵

Surgery of GISTs has been modified concomitant with advances in our understanding of the molecular pathogenesis of GISTs. Previously, the principle of surgical treatment of smooth muscle tumors was local excision with a 2-cm margin of the surrounding GI wall.⁶ However, large margins of this size are unnecessary because GISTs usually grow out of the primary organ, rather than being diffusely infiltrating. Because the microscopic margin and routine lymphadenectomy have not been associated with improved oncologic outcomes,^5,7 these factors provided justification for laparoscopic surgery of GISTs.⁸ Laparoscopic surgery was considered a less invasive procedure than open surgery. In 1992, Lukaszczyk and Preletz⁹ first introduced laparoscopic resection of benign stromal tumors of the stomach. In the last decade, laparoscopic surgery for GISTs has improved and gained increasing importance. Several case series have proved the safety and feasibility of laparoscopic resection of GISTs; however, the benefits for oncologic results have not been widely reported. In the current study, we retrospectively reviewed data for GIST patients who underwent laparoscopic surgery and traditional open surgery at our hospital between 2005 and 2010. The clinical data, benefits of operation, perioperative outcomes, and oncologic outcomes were reviewed.

Patients and Methods

Clinical data for 227 GIST cases pathologically diagnosed at the Chang Gung Memorial Hospital at Linkou, Taipei, Taiwan, between 2005 and 2010 were retrospectively reviewed. We excluded the following patients: those with tumor sizes above 5 cm assessed by preoperative imaging (n=81); biopsy alone (n=11) or concomitant with other resections (n=23); those with endoscopic mucosal resection (n=6); those with tumors located in the duodenum (n=15), colon–rectum (n=14), esophagocardiac junction (n=1), omentum (n=1), pelvis (n=1), and retroperitoneum (n=12); those with observable metastasis during the operation (n=1); and those diagnosed as other disease after immunohistochemical examination (n=3). Thus, we excluded 169 cases and included only 58 cases. Patients with stomach GIST were diagnosed using a gastroscope (n=40), and those with small bowel GIST were diagnosed using abdominal computed tomography (n=11) and double-balloon enteroscopy (n=7).

Of the 58 selected patients, 16 received laparoscopic surgery, and 42 received open surgery. All patients had elective surgery, and none of the 58 cases had active bleeding with unstable vital signs. The choice of surgical method (laparoscopic or open) was dependent on the surgeons' preference. The demographic characteristics of the patients, including age, sex, tumor size, tumor location, co-morbidity, and the American Society of Anesthesiologists (ASA) score, were recorded. For laparoscopic resection, patients were placed in the supine position and under general anesthesia. A 10-mm laparoscope was inserted through the umbilical port. The position of the patients was adjusted to the reverse Trendelenburg or decubitus position, as required. For patients with small bowel GISTs, two additional paramedian 5-mm ports were added for identification of the lesions. Once the tumor was identified, the lesion was exteriorized out of the peritoneal cavity through a minilaparotomy wound with a wound protector/retractor. Resection and anastomosis were performed extracorporeally. For patients with stomach GISTs, an additional 12-mm right midaxillary port was placed. After wedge resection using an Endo GIA™ stapler (Covidien), the tumor was placed in a laparoscopic specimen bag and retrieved from the umbilical trocar wound with or without extension. Subtotal gastrectomies were performed using the same four trocars. We performed extracorporeal Billroth I anastomosis using a wound protector/retractor. In open surgery patients with subtotal gastrectomies, reconstruction was performed by Billroth II anastomosis. The choice of reconstructive method was based on the surgeons' preference. All patients were allowed patient-controlled analgesia (PCA) preoperatively. Nonetheless, when patients were prepared for laparoscopic resection, they were informed by the surgeons that the pain is similar to that experienced during laparoscopic cholecystectomy and that PCA is rarely needed. However, patients were free to decide whether PCA was required before and after surgery. Patients who did not chose PCA were offered a narcotic analgesic (meperidine) for pain relief. The perioperative characteristics and pathologic and oncologic results were recorded and analyzed. The pathologic risk classification was based on the risk table of Miettinen and Lasota.¹⁰ Patients who were converted from laparoscopic surgery to traditional laparotomy were included as the laparoscopic group. Patients had abdominal computed tomography scans at follow-up every 3 months in the first 2 postoperative years, every 6 months in the following 3 years, and annually afterward.

Statistical Analysis

The Mann–Whitney test was used to compare nonordinal parameters, and the chi-squared test was used to compare ordinal parameters. A value of P<.05 was considered statistically significant.

Results

The mean age of the study group (58 patients) was 58.5 years, and 55.2% were women. There were 16 patients in the laparoscopic surgery group (LSG) and 42 in the open surgery group (OSG). No concurrent resection was observed in our study. The demographic data for the patients are summarized in Table 1. No intergroup differences in age, gender, and co-morbidities were observed. Furthermore, there were no intergroup differences in ASA scores. The mean tumor sizes in the LSG and OSG were 3.42 cm (range, 1.2–5.4 cm) and 3.78 cm (range, 0.8–6 cm), respectively. The mean sizes of the stomach GISTs (n=40) and small bowel GISTs (n=18) were 3.52 cm (range, 0.8–6 cm) and 4.04 cm (range, 1.2–6 cm), respectively. There was no significant intergroup difference in tumor size with compatible tumor locations.

Table 1.

Demographic and Clinical Characteristics of Patients

	Laparoscopic surgery (n=16)	Open surgery (n=42)	P value
Age (years) [mean (range)]	56.44 (40–84)	59.31 (20–86)	.375
Sex (M:F)	7:9 (43.8%:56.2%)	19:23 (45.2%:54.8%)	.919
Co-morbidity
Diabetes mellitus	1 (6.3%)	8 (19.0%)	.229
Hypertension	6 (37.5%)	18 (42.9%)	.711
Heart disease	3 (18.8%)	6 (14.3%)	.675
Cerebrovascular disease	0 (0%)	3 (7.1%)	.272
Obstructive lung disease	1 (6.3%)	2 (4.8%)	.819
Liver cirrhosis	1 (6.3%)	0 (0%)	.102
Renal insufficiency	1 (6.3%)	2 (4.8%)	.819
Previous abdominal surgery	1 (6.3%)	2 (4.8%)	.819
Other	3 (18.8%)	10 (23.8%)	.680
Tumor size (cm) [mean (range)]	3.42 (1.2–5.4)	3.78 (0.8–6)	.266
ASA			.098
ASA I	0%	7 (16%)
ASA II	12 (75%)	20 (47.6%)
ASA III	4 (25%)	15 (35.7%)
Tumor location			.696
Upper third of stomach	6 (37.5%)	19 (45.2%)
Middle third of stomach	1 (6.3%)	2 (4.8%)
Lower third of stomach	2 (12.5%)	10 (23.8%)
Jejunum	6 (37.5%)	10 (23.8%)
Ileum	1 (6.3%)	1 (2.4%)

ASA, American Society of Anesthesiologists; F, female; M, male.

The perioperative characteristics are shown in Table 2. Of LSG patients, 6.3% received subtotal gastrectomy, 50% received wedge resection, and 43.8% received small bowel resection. One case was converted to open surgery (6.25%) because of failure in localizing the tumor during laparoscopic examination. Of OSG patients, 9.5% received subtotal gastrectomy, 69.1% received wedge resection, and 21.4% received segmental bowel resection. In addition, no tumor perforation was noted both intraoperatively and by microscopic examination postoperatively in both the groups. We achieved microscopic R0 resection of surgical margins in all LSG patients, whereas 7.1% (n=3) of OSG patients were microscopically margin-positive. However, there were no significant intergroup differences in margin-positivity rate. The mean operative times for the LSG and OSG were 127.44 and 132.59 minutes, respectively. The estimated blood loss was 12.50 and 20.24 mL in the LSG and OSG, respectively. The operative time and estimated blood loss were similar in both the groups.

Table 2.

Operation Methods

	Laparoscopic surgery (n=16)	Open surgery (n=42)	P value
Subtotal gastrectomy	1 (6.3%)	4 (9.5%)	.235
Wedge/wide resection of tumor	8 (50%)	29 (69.1%)
Segmental bowel resection	7 (43.8%)	9 (21.4%)
Operation time (minutes) [mean (range)]	127.44 (66–253)	132.59 (50–267)	.763
Bleeding (mL) [mean (range)]	12.50 (0–100)	20.24 (0–250)	.699
Positive margin	0 (0%)	3 (7.1%)	.272
Conversion	1/16 (6.25%)

Postoperatively, there was no significant difference in flatus passage days and narcotics dosage (Table 3). Nevertheless, LSG patients resumed diet after a fewer number of days, had shorter postoperative hospital stays, and had lower demand for PCA than OSG patients. The postoperative morbidity in LSG was 6.3% (n=1) because of ileus. The morbidity in OSG was 19%, including ileus (n=2), ventral hernia (n=1), surgical site infection (n=1), urinary tract infection (n=1), sepsis of unknown focus (n=1), prolonged fever due to atelectasis (n=1), and GI bleeding (n=1). We chose not to further repair the ventral hernia, and all other patients received conservative treatment without receiving invasive procedures to resolve postoperative morbidity. Although the morbidity rate was higher in OSG than in LSG, the difference was not statistically significant. Furthermore, no postoperative mortality was observed in both groups.

Table 3.

Operative and Perioperative Outcomes

	Laparoscopic surgery (n=16)	Open surgery (n=42)	P value
Flatus (days) [mean (range)]	3.25 (2–5)	3.38 (1–5)	.644
Days to resume diets (days) [mean (range)]	5 (2–11)	5.71 (3–10)	.023
Postoperative stay (days) [mean (range)]	8 (4–13)	9.07 (6–13)	.038
Analgesia use
PCA (yes:no)	1:15	20:22	.004
Narcotic analgesic (dose) [mean (range)]	1.76 (0–6.4)	2.54 (0–16.0)	.838
Morbidity	1 (6.3%)	8 (19.0%)	.229
Mortality	0	0

PCA, patient-controlled analgesia.

The pathological characteristics and oncological results are shown in Table 4. There was no difference in the risk classification based on the postoperative evaluation of tumor size and mitotic index. There were 5 high-risk patients (LSG, 2; OSG, 3), and none of them was administered imatinib after surgery. The follow-up time was 14.83–77.13 months (median, 32.73 months) in LSG and 0.83–80.93 months (median, 39.75 months) in OSG. Recurrence or metastases were observed in 3 patients (LSG, 1; OSG, 2). No significant differences in intergroup recurrence rates were observed (LSG versus OSG, 6.3% versus 4.8%, respectively; P=0.821). All patients survived until the last follow-up, which was at the end of December 2011.

Table 4.

Pathologic Variables and Clinical Outcome

	Laparoscopic surgery (n=16)	Open surgery (n=42)	P value
Follow-up time (months) [median (range)]	32.73 (14.83–77.13)	39.75 (0.83–80.93)	.486
Risk			.158
Very low	7 (43.8%)	8 (19.0%)
Low	6 (37.5%)	22 (52.4%)
Intermediate	1 (6.3%)	9 (21.4%)
High	2 (12.5%)	3 (7.1%)
Recurrence	1 (6.3%)	2 (4.8%)	.821
Overall survival	No mortality	No mortality

Discussion

Although imatinib is important in GIST therapy, surgery has always been the mainstay of GIST treatment.^11–13 Surgery is curative in over 97% of GIST patients with very low, low, or intermediate risk. In the high-risk group, complete resection was achieved in 80% of patients, of whom 37.5% became disease-free within a median follow-up time of 8 years, and 62.5% showed recurrence or metastasis.¹⁴ The prognosis of GIST after surgical treatment is influenced by the malignant potential of the tumor and completeness of the primary resection.¹⁵ Adjuvant treatment with imatinib after surgical resection is recommended for patients with high-risk GISTs.¹⁶

Since the first minimally invasive surgery (laparoscopic cholecystectomy) was performed in 1988, various procedures have been established, and a large variety of instruments have been innovated to overcome the technical challenges of minimally invasive procedures. Laparoscopic cholecystectomy is currently the gold standard for symptomatic cholecystolithiasis. Increasing numbers of complicated minimally invasive procedures are being used routinely instead of open surgeries. This less invasive approach provides lesser wound pain, shorter hospital stays, and quicker recoveries in benign diseases.¹⁷ In our study, 20 of 42 patients (47.6%) required PCA for relieving postoperative pain in OSG. On the other hand, the PCA demand was significantly lower in LSG (6.67%). Considering postoperative recovery, there was a significant improvement in days to resumption of diet (5 versus 5.71 days, respectively) and number of days of postoperative hospital stay (8 versus 9.07 days, respectively) in LSG versus OSG. These results showed that minimally invasive procedures for resection of GISTs offered less pain and early recovery.

During laparoscopic surgery, technical difficulties, such as tumor localization, obtaining defined resection margins, laparoscopic anastomosis of the GI tract, and adhesiolysis, may be encountered. Intraoperative tumor localization may be difficult, especially in cases with complete intraluminal lesions, because of lack of sharp tactile sensations in open surgery. To overcome this problem, we performed double-balloon enteroscopic tattooing of small bowel lesions in 7 patients with small bowel tumors in LSG.¹⁸ Only 1 case was converted to open surgery because of difficulty in tumor localization during laparoscopic examination.

Although the principle of surgical oncology is to obtain free resection margins both macro- and microscopically, the value of the negative microscopic margins on the resected organ is uncertain with large GISTs, according to the National Comprehensive Cancer Network (NCCN) 2007 guidelines. Several authors also showed that a microscopically negative margin is not an independent factor predictive of disease-free survival.^4,5 In a review of the literature, we found that the overall positive margin rate was 6/785 (0.76%) in all the different approaches. We had 3 cases with positive margins in OSG and, fortunately, no cases with positive margins in LSG. The status of all the 3 patients with positive margins was discussed with our GIST multidisciplinary team and the patients. No further re-excision was arranged, and the patients did not show recurrence, at least until the last follow-up.

Theoretically, GISTs of any size can be laparoscopically operated on. The NCCN and the European Society of Medical Oncology released consensus statements in 2004 recommending that a laparoscopic resection may be acceptable for small intramural tumors (size, <2 cm) but should be avoided for large tumors.¹⁹ However, the NCCN guidelines were modified in 2007, to state that tumors up to size 5 cm could be safely resected laparoscopically, and even larger tumors could be considered for laparoscopic resection via the hand-assisted approach.²⁰ Several studies have reported case series with laparoscopic resections of GISTs with tumor sizes above 10 cm.^21–23 Bulky tumors may obscure exposure of the surgical field, and the risk for tumor rupture is increased, owing to either poor visualization or limited gentle dissection because of lack of fine tactile sensation, as in the case of open surgery. Large tumors usually need a large laparotomy wound (diameter, ≥6–7 cm) to extract the tumor. Morcellation of large GISTs may result in inaccurate measurement of the actual tumor size, leading to erroneous risk. Furthermore, morcellation of the tumor may increase the risk of intra-abdominal and port-site recurrence. Kim et al.²⁴ reported a case of port-site recurrence in the abdominal wall after previous laparoscopic wedge resection of gastric GIST at 35 months postoperatively. They suggested that with the increasing size of the GIST, repeated passage of instruments and increased manipulation of the tumor may lead to exfoliation of tumors, which could induce postoperative recurrence. Therefore, we suggest that laparoscopic surgery should be performed on tumor sizes of not more than 5 cm, confirmed by preoperative image survey, as suggested in the NCCN guidelines.

Wide exposure of the surgical field and the resulting shorter operation time are considered safer and primary for oncologic surgery, especially for patients in poor general condition. Laparoscopic surgery was thought to limit wide exposure of the surgical field and to increase the time for operation. Several reports have demonstrated that laparoscopic approaches are safe and feasible for elderly patients with co-morbidities. Cui et al.²⁵ reviewed 4048 cases of laparoscopic cholecystectomy, where 18% of the patients were of elderly category and had high ASA scores (III and IV). Their results showed no difference in operative time, intraoperative complications, and mortality in these elderly patients compared with those in younger patients. Choi et al.²⁶ also reported a series in laparoscopic-assisted distal gastrectomy with systemic comorbidity (ASA scores of II, III, and IV). Their data also showed no increasing operative risk and reduction in advantages provided by minimally invasive surgery in patients with high ASA scores compared with patients with ASA I score. In our current study, 4 patients who received laparoscopic resection of GIST had ASA score III and had uneventful postoperative courses. The operative time and intraoperative blood loss were similar in both study groups. Therefore, we assume that with preoperative evaluation and planning of surgery, followed by the use of improved technology and surgical instruments, high ASA scores need not be a limitation for laparoscopic surgery.

Among oncologic surgeries, laparoscopic surgery for early gastric cancer provides better short-term outcome, with less blood loss, early recovery, less analgesia application, and no marked increase in morbidity or mortality than those by open surgery. Fewer surgical complications were observed in LSG than in OSG. For long-term oncological results, the 5-year disease-free survival rate was excellent in LSG and in OSG, which encouraged both Japanese and Korean surgeons to extend the indications to more advanced diseases.^27,28 Although the perioperative complications were not statistically significant, these complications were lower in LSG than in OSG (6.3% versus 19%, respectively); in particular, fewer septic and wound complications were observed in LSG. Novitsky et al.²⁹ reported a case series with 50 patients who underwent laparoscopic or laparoendoscopic resection of gastric GISTs with mean tumor size of 4.4 cm. All 50 patients had negative resection margins, and disease-free survival was observed in 92% of the patients during the 36-month follow-up. Karakousis et al.³⁰ presented a size-matched comparison of laparoscopic resection (n=40) with open resection (n=40) for GIST patients. In their medical follow-up at 28 months in LSG and 43 months in OSG, only two recurrences were noted (one in each group). Furthermore, there were 5 high-risk patients in our study (LSG, 2; OSG, 3). Although adjuvant therapy with imatinib is the current standard of care for high-risk GISTs, our national insurance approved this therapy only after 2011. Therefore, none of the patients in our study received postoperative imatinib therapy.

The results showed good oncologic outcome in both LSG and OSG. In this study, three recurrences (LSG, one; OSG, two) were observed during follow-up. All recurrent tumors were located in the small bowel, and the patients underwent small bowel resections. None of the patients was margin positive or had tumor perforations during surgery. In LSG, the patient with recurrence was a 68-year-old woman with a 3-cm jejunal GIST defined as high risk by mitotic count (>10/50 under high-power field). Liver metastasis was identified at 14 months postoperatively. In OSG, one of the patients with recurrence was a 35-year-old woman with a 5.5-cm jejunal GIST defined as intermediate risk by mitotic count (<5/50 under high-power field). Supravesical pouch recurrence was observed at 7 months postoperatively. The other recurrence in OSG was in a 56-year-old man with 4.5-cm ileal GIST defined as a low-risk tumor by mitotic count (4/50 under high power field). Multiple metastases were observed in the liver and pelvic cavity 28 months postoperatively. All 3 patients were administered imatinib (400 mg/day) and showed partial response until the last follow-up. There was no difference in intergroup recurrence rate. Thus, these results show that LSG shows short-term oncologic outcome and that laparoscopic surgery could, therefore, be applied widely in stomach and small bowel GISTs.

Conclusions

Laparoscopic surgery was technically feasible for GISTs of size not more than 5 cm, assessed by preoperative imaging studies and located at the nonesophagocardiac junction of the stomach and small bowel. The rate of conversion from laparoscopic to open surgery was as low as 6.25%, only in the early learning curve. Laporoscopy offers the same operative time and blood loss as in open surgery, but it offers a safe microscopic margin. Although not statistically significant, the morbidity was lower in LSG. With careful patient selection, laparoscopy could be performed safely for patients with high ASA scores. We showed that laparoscopic resection of GISTs had the following benefits: fewer days to resume diet, shorter postoperative stay, and less analgesia use during the perioperative period. Future studies, including case-based controls with the same disease region, may help evaluate the oncologic benefits of laparoscopy.

Footnotes

Disclosure Statement

No competing financial interests exist.

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