# Perioperative and Oncological Outcome of  Laparoscopic Resection of Gastrointestinal Stromal  Tumour (GIST) of the Stomach

Authors: Ulrich Ronellenfitsch; Wilko Staiger; Georg Kähler; Philipp Ströbel; Matthias Schwarzbach; Peter Hohenberger
Journal: Diagnostic and Therapeutic Endoscopy
 (2009)

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## Abstract

Background. Surgery remains the only curative treatment for gastrointestinal stromal tumour (GIST). Resection needs to ensure tumour-free margins while lymphadenectomy is not required. Thus, partial gastric resection is the treatment of choice for small gastric GISTs. Evidence on whether performing resection laparoscopically compromises outcome is limited. Methods. We compiled  patients undergoing laparoscopic resection of suspected gastric GIST between 2003 and 2007. Follow-up was performed to obtain information on tumour recurrence. Results. Laparoscopic resection with free margins was performed in 21/22 patients. Histology confirmed GIST in 17 cases, 4 tumours were benign neoplasms. Median operation time and postoperative stay for GIST patients were 130 (range 80–201) mins and 7 (range 5–95) days. Two patients experienced stapler line leakage necessitating surgical revision. After median follow-up of 18 (range 1–53) months, no recurrence occurred. Conclusions. Laparoscopic resection of gastric GISTs yields good perioperative outcomes. Oncologic outcome needs to be assessed with longer follow-up. For posterior lesions, special precaution is needed. Laparoscopic resection could become standard for circumscribed gastric GISTs if necessary precautions for oncological procedures are observed.


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## Body

## 1. Introduction

Gastrointestinal stromal tumours (GISTs) are the most
common mesenchymal neoplasms of the digestive tract with an estimated annual
incidence of 10–20 cases per one
million inhabitants [1, 2]. GISTs
probably arise from precursor cells of the interstitial cells of Cajal. Their
defining characteristic is a gain-of-function mutation in genes coding for the
KIT tyrosine kinase receptor, which is considered the driving force of cell
proliferation in this tumour [3]. Clinical
presentation of GISTs ranges from indolent, hardly proliferating to
fast-growing, recurring and metastasising tumours [1]. Fletcher et
al. proposed a classification of aggressive behaviour for GISTs based on their
maximum diameter and mitotic rate [4]  (Table 1),
factors which were both shown to predict recurrence and survival [5, 6].Table 1
Classification of aggressive behaviour of GISTs
proposed by Fletcher et al. [4].
Tumour size (largest diameter)Mitotic count per 50 high power fieldsVery low risk<2 cm<5Low risk2–5 cm<5Intermediate risk<5 cm6–105–10 cm<5High risk>10 cmany numberany size>10>5 cm>5Treatment of choice for primary GISTs remains complete resection.
Whereas current National Comprehensive Cancer Network (NCCN) guidelines [7] recommend surgery for GISTs or
supposed GISTs of any size, the latest European Society for Medical Oncology
(ESMO) Clinical Recommendations stipulate frequent surveillance without surgery
for lesions with a diameter below 2 cm [8]. In contrast to resection of
intestinal carcinomas, surgery of GISTs does not require lymphadenectomy since
lymphatic metastatic spread is extremely rare in primary tumours [1]. Thus, local resection of the
tumour with clear margins is recommended. Moreover, strict avoidance of
intraoperative tumour rupture is crucial for preventing tumour relapse.About 50% of GISTs are located in the stomach which makes it the most
frequent site of manifestation [2, 9]. Due to the often fragile
consistence, particularly of pedunculated GISTs, there is an ongoing debate
whether surgical resection of gastric GISTs can be performed laparoscopically
without increasing perioperative morbidity and compromising oncological
outcome. The latest ESMO Clinical Recommendations consider a laparoscopic
approach “if cancer surgery principles are respected.” [8] Current NCCN guidelines do not contain a clear
statement on whether surgery for GIST should be performed laparoscopically or
through open surgery but recommend that surgery should produce minimal surgical
morbidity [7].The present study tries to evaluate whether laparoscopic resection of
gastric GISTs can become a standard treatment for such tumours by analysing
perioperative characteristics and long-term oncological outcome.


## 2. Material and Methods

### 2.1. Study Population and Data Analysis

The study includes all patients who underwent laparoscopic resection of
a primary tumour of the stomach deemed to be a GIST on clinical assessment
between January 1, 2003, when a laparoscopic approach became our standard for
the described lesions, and December 31, 2007. Patients were eligible for
laparoscopic surgery if preoperative staging (endoscopy, endosonography and CT
scan) showed a localised, non-metastatic extramucosal gastric lesion. Tumours
were required to be of a diameter and in a position which suggested
resectability through segmental or wedge resection. Preoperative histological
confirmation of the diagnosis was not a prerequisite for inclusion.
Histological diagnosis of GIST was obtained from the resection specimen by
means of hematoxylin and eosin staining and immunohistological assays for CD117
and CD34 and platelet-derived growth factor receptor alpha. Mutational analysis
was performed where required.From a prospectively kept database, we extracted the following
characteristics: age, sex, length of postoperative hospital stay, operation
time, tumour location, tumour size, classification of aggressive behaviour as
defined in Table1, histopathological assessment of resection margins,
intraoperative blood loss, and incidence of perioperative complications
(cardiac, pulmonary, septic, anastomotic failure, reoperation needed). We
present single values as well as the median plus range or, where applicable,
percentages, for the respective variables.All patients with confirmed GIST were followed up regularly including
upper GI endoscopy and abdominal CT scans every three to six months depending
on the risk for malignant behaviour. From these visits we assessed vital status
and tumour recurrence. A few patients with very low-risk GIST decided against
adhering to this program and were followed up through phone calls to their
general practitioner or themselves. In the former case, the family physician
was asked when the patient had last presented and if to his knowledge any
recurrence of the tumour was known. The same question was asked directly to
patients in case their family physician was not available. Date of follow-up
was ascertained either as the date of the patient's last visit to our
outpatient clinic or the date of the phone call to the family physician or
patient, respectively.


### 2.2. Surgical Methodology

All laparoscopic resections were performed in a standardised manner. The
patient was placed in supine position with legs spread and a four-port
technique was used. After visual and tactile control of the liver and the
abdominal cavity for metastases, the lesion was identified through
visualisation and palpation. In case of tumour location at the posterior wall
of the stomach, the gastrocolic ligament was dissected and the stomach inverted
in order to display the lesion. If necessary, intraoperative endoscopy was
performed to elevate the tumour and stain its margins with ink (Figure1). The
tumour-bearing gastric segment was resected with one or several 45 mm
endoscopic linear staplers. The resection specimen was placed into a plastic
retrieval bag and removed through one of the port incisions. Stapler lines were
visually controlled and, if deemed necessary by the surgeon, their integrity
was assessed through the application of methylene blue via a nasogastric tube.
If the lines showed leakage or were deemed to be at risk for it, additional
manual sewing of the line was performed. A postoperative control of stapler
lines by means of endoscopy or CT scan after oral intake of contrast medium was
only done in case of clinical suspicion of leakage.Figure 1
Endoscopic ink staining of tumour
margins.


## 2.1. Study Population and Data Analysis

The study includes all patients who underwent laparoscopic resection of
a primary tumour of the stomach deemed to be a GIST on clinical assessment
between January 1, 2003, when a laparoscopic approach became our standard for
the described lesions, and December 31, 2007. Patients were eligible for
laparoscopic surgery if preoperative staging (endoscopy, endosonography and CT
scan) showed a localised, non-metastatic extramucosal gastric lesion. Tumours
were required to be of a diameter and in a position which suggested
resectability through segmental or wedge resection. Preoperative histological
confirmation of the diagnosis was not a prerequisite for inclusion.
Histological diagnosis of GIST was obtained from the resection specimen by
means of hematoxylin and eosin staining and immunohistological assays for CD117
and CD34 and platelet-derived growth factor receptor alpha. Mutational analysis
was performed where required.From a prospectively kept database, we extracted the following
characteristics: age, sex, length of postoperative hospital stay, operation
time, tumour location, tumour size, classification of aggressive behaviour as
defined in Table1, histopathological assessment of resection margins,
intraoperative blood loss, and incidence of perioperative complications
(cardiac, pulmonary, septic, anastomotic failure, reoperation needed). We
present single values as well as the median plus range or, where applicable,
percentages, for the respective variables.All patients with confirmed GIST were followed up regularly including
upper GI endoscopy and abdominal CT scans every three to six months depending
on the risk for malignant behaviour. From these visits we assessed vital status
and tumour recurrence. A few patients with very low-risk GIST decided against
adhering to this program and were followed up through phone calls to their
general practitioner or themselves. In the former case, the family physician
was asked when the patient had last presented and if to his knowledge any
recurrence of the tumour was known. The same question was asked directly to
patients in case their family physician was not available. Date of follow-up
was ascertained either as the date of the patient's last visit to our
outpatient clinic or the date of the phone call to the family physician or
patient, respectively.


## 2.2. Surgical Methodology

All laparoscopic resections were performed in a standardised manner. The
patient was placed in supine position with legs spread and a four-port
technique was used. After visual and tactile control of the liver and the
abdominal cavity for metastases, the lesion was identified through
visualisation and palpation. In case of tumour location at the posterior wall
of the stomach, the gastrocolic ligament was dissected and the stomach inverted
in order to display the lesion. If necessary, intraoperative endoscopy was
performed to elevate the tumour and stain its margins with ink (Figure1). The
tumour-bearing gastric segment was resected with one or several 45 mm
endoscopic linear staplers. The resection specimen was placed into a plastic
retrieval bag and removed through one of the port incisions. Stapler lines were
visually controlled and, if deemed necessary by the surgeon, their integrity
was assessed through the application of methylene blue via a nasogastric tube.
If the lines showed leakage or were deemed to be at risk for it, additional
manual sewing of the line was performed. A postoperative control of stapler
lines by means of endoscopy or CT scan after oral intake of contrast medium was
only done in case of clinical suspicion of leakage.Figure 1
Endoscopic ink staining of tumour
margins.


## 3. Results

22 patients had been planned for laparoscopic segment resection
of a suspected gastric GIST. Out of these, 21 were resected with the technique.
In one patient, conversion to laparotomy was necessary due to extensive
intraabdominal adhesions with the larger omentum completely fixed to the
ventral abdominal wall. This patient was not included in the analysis. One of
the 21 patients had received preoperative imatinib treatment for a GIST with a
diameter of 8 cm. He had adverse characteristics for open surgery (pronounced
obesity) and was reluctant to undergo any resection at first. Neoadjuvant
imatinib caused a reduction of tumour size which enabled a laparoscopic
approach to which the patient finally agreed. Histology confirmed a GIST in 17
of 21 cases. In one case histological workup showed pancreatic heterotopy, in
one case leimoyoma, in one case gastric schwannoma, and in one case gastric
wall lipoma.Table2 provides perioperative characteristics of the 17 GIST patients
in which the intervention could be performed laparoscopically. Both sexes were
equally represented and most patients were in their sixth or seventh decade of
life (age range 43–79 years).
Tumours were located in all parts of the stomach with a predominance of the
corpus and antrum. All tumours were resected with negative margins and there
was no intraoperative tumour rupture. Intraoperative blood loss was below 200 mL
in all patients and no patient required blood transfusion. The median duration
of surgery was 130 (range 80–201) minutes and
the median postoperative hospital stay 7 (range 5–95) days. In two
patients, a postoperative complication occurred: one early stapler line leakage
requiring laparotomy for re-suturing and one late stapler line leakage which
led to a prolonged hospital stay and finally resulted in Billroth II
gastrectomy. Both patients were obese (BMI  > 30) and in both cases the tumour
was located on the posterior stomach wall. In the former case, the leakage
occurred on postoperative day 1 when the patient presented with severe
abdominal pain and preseptic conditions. Diagnosis was made by application of
methylene blue through the nasogastric tube and its detection through the
indicative drainage which was still in place. The patient was immediately
re-operated through a small laparotomy and the further clinical course was
uneventful except for subcutaneous wound infection. The latter patient was
first treated with re-laparoscopy on postoperative day 6 for removal and
drainage of an intraabdominal abscess. On postoperative day 10, leakage was
detected endoscopically and treated with endoluminal stenting. After gradual
clinical improvement the patient was discharged on day 61 but was re-admitted
few days later with peritonitic signs. Releakage was diagnosed and open
subtotal gastrectomy had to be performed. Finally, the patient was discharged
in good clinical condition 95 days after initial surgery.Table 2
Perioperative and tumour characteristics of the patients.
PatientSexAgeTumour localisationHistologyMax. tumour diameter (cm)Mitotic figures/50 HPFRisk classification§Duration of surgery (minutes)Postop. hospital stayPostoperative morbidity1m45fundusGIST5<5low1655none2m79fundusGIST42low947none3*f43anterior corpusGIST0.8<5very low895none4f56greater curvature/ant. corpusGIST1.75very low1756none5f55lesser curvatureGIST5.42intermediate1136none6m59posterior antrumGIST3.53low16195late stapler line leakage
resulting in B-II-gastrectomy7f74lesser curvatureGIST2.1<5low1307none8m45anterior antrumGIST2.51low1736none9f72greater curvature/post. corpusGIST5.1<5intermediate33312early stapler line leakage resulting in resuturing through laparotomy10f52anterior corpusGIST2<2low1256none11f46greater curvature/ant. corpusGIST2.13low807none12#f66antrumGIST2.92low1129none13m82lesser curvatureGIST10<5intermediate18514none14m62posterior corpusGIST2<2very low2018none15m64anterior antrumGIST6<5intermediate1056none16*f67lesser curvatureGIST1.8<5very low18410none17$m66anterior corpusGIST4n/an/a1438nonemediann/a56n/an/a2.9n/an/a1307n/an/a: not applicable.*Additional cholecystectomy for
cholecystolithiasis. #Additional liver cyst deroofing. $Due
to preoperative imatinib treatment classification of
aggressive behaviour not possible. §see Table 1.Table3 shows the results of the follow-up. After a median period of 18
(range 1–53) months, in
none of the patients recurrence or distant metastases had been detected and all
patients were alive. In patients with an intermediate risk GIST, median
follow-up was 18 (range 6–46) months.Table 3
Results of the follow-up of operated patients.
PatientSexAgeClassification of aggressive behaviour§Follow-up (months)Tumour recurrence, metastases or death at end of follow-up?1m45low44no2m79low40no3f43very low18no4f56very low27no5f55intermediate23no6m59low14no7f74low9no8m45low6no9f72intermediate6no10f52low53no11f46low10no12f66low12no13m82intermediate46no14m62very low47no15m64intermediate18no16f67very low1no17$m66intermediate/high5nomediann/a59n/a18n/an/a: not applicable;§see Table 1; $received preoperative imatinib treatment.
Aggressive behaviour classified based on pre-treatment staging.


## 4. Discussion

The main principle of curative surgery for GISTs is en bloc resection
with negative tumour margins and strict avoidance of intraoperative tumour
rupture. Due to the extremely low frequency of lymphatic metastasis,
lymphadenectomy is not required. Thus, segmental or wedge resection is the
treatment of choice for tumours whose size and location technically allow for
it [10, 11]. The aims of the present analysis
were to assess if the mentioned surgical principles could be sufficiently met
with a laparoscopic approach and to evaluate perioperative and oncological
outcomes of patients resected with this method.In line with previously published case series [12–28], our results support the
application of laparoscopy for wedge resection of gastric GISTs. In all but one
case deemed eligible for the procedure based on staging exams, the intervention
could be performed without conversion to laparotomy. Resection with tumour-free
resection margins was possible in all cases and there were no instances of
intraoperative tumour rupture. Although there are no respective empirical data,
we consider the usage of a retrieval bag for the removal of the surgical
specimen essential in order to avoid spillage of tumour cells into the
abdominal cavity or port sites, thus preventing metastasis. Even small GIST of
2-3 cm in size
harbour the risk of malignant behaviour and consequently tumour resection
should be performed according to standards of laparoscopic resection for GI
malignancies.In our series, overall perioperative morbidity was low with virtually no
blood loss and satisfying operation times. As in other laparoscopic procedures,
the existence of a “learning curve” must be assumed and it can be expected that
operation times further decrease with growing experience [29–31]. The median length of hospital stay
of our patients was relatively short, too. It can be speculated that patients
could have been discharged even earlier and that the relatively lengthy stay
was attributed to the rather recent introduction of the methodology at our
centre.In two patients, severe postoperative morbidity occurred due to leakage
from the stapler line. In both cases, the tumour was partially located at the
posterior wall of the stomach, and both patients were obese (BMI  > 30). In
such patients, laparoscopic resection is particularly challenging because it
requires extended mobilisation of the stomach and preparation through the
omental bursa, hampered by impaired visibility of the operation field.
Technical difficulties in stapling and/or suturing might be the consequence.
Both leakages led us to the routine use of fleece patches to strengthen the
suture line and we strongly recommend their application in patients with the
characteristics described. An alternative for the resection of lesions of the
posterior gastric wall, especially for lesions located close to the
gastro-esophageal junction, could be a transgastric approach through anterior
gastrotomy [15, 20, 32–34]. This technique, however, is
technically even more demanding [20], and there are reports of
postoperative complications [32] and incomplete tumour resections [35]. As a complementary method, a
combined endoscopic-laparoscopic approach can be used. We have applied this
technique in several cases to facilitate tumour identification and lifting into
the stapler predominantly in relatively small and non-protruding lesions. Its
utility for resection of gastric GIST, especially for tumours in the proximal
posterior part of the stomach, has been reported in several series [28, 36, 37]. Recently, a new technique of
endoscopic full-thickness resection using a flexible stapler was described.
This approach seems particularly useful in tumours of the posterior distal part
of the stomach [38].In summary, we do not consider any tumour location as a strict
contraindication towards laparoscopy if the necessary experience is given and
if the required precautions are met. Several additional technical approaches
can be used to facilitate safe resection. Nevertheless, it is important to
emphasize that the threshold for laparotomy should be rather low if
intraoperative difficulties are encountered.One concern about wedge resection of the stomach is the occurrence of
postoperative gastric stenosis, especially when parts of the gastro-oesophageal
junction or the pylorus are resected [17, 20, 23]. In our patients, we did not find
any early postoperative stenosis. There were, however, only six cases where the
tumour was located in the antrum and none with a tumour directly at the
gastro-oesophageal junction. With regard to long-term functional results, we
were not confronted with symptoms or endoscopical signs of reflux or stenosis
during postoperative follow-up.For tumours with a larger diameter and/or unfavourable location, primary
wedge resection is often not possible and total or subtotal gastrectomy would
be required for resection with tumour-free margins. For these cases, the NCCN
guidelines [7] and ESMO recommendations [8] suggest neoadjuvant imatinib
therapy to decrease tumour size, thus allowing for organ-preserving surgery.
The feasibility and outcomes of this approach are currently evaluated in
several clinical trials [39]. Our case series includes one
patient who received six months of neoadjuvant imatinib treatment in the
framework of the C
STI571 BDE 43 trial, (“Apollon study”) [11]. Laparoscopic resection of an
originally large GIST of the anterior corpus was made possible in this case
thanks to a considerable shrinkage of the tumour.In our series, 4 out of 21 tumours preoperatively suspected to be a GIST
were histologically diagnosed as pancreatic heterotopia, gastric lipoma,
schwannoma, and leiomyoma. Retrospectively, in these cases surgical resection
would have not been required for oncological reasons. Preoperative histological
diagnosis of submucosal gastric lesions is however not always feasible through
endoscopic biopsy. Moreover, biopsy seems to be associated with a certain risk
of tumour haemorrhage and dissemination [1]. Modern imaging techniques such as
endosonography or CT gastrography with 3D reconstruction [40] can aid in making the preoperative
diagnosis without being invasive towards the tumour. Nevertheless, a clear
preoperative diagnosis will still not be possible in all cases of submucosal
gastric tumours. We think that it is warranted to perform surgical excision of
submucosal gastric lesions without prior histological ascertainment even if in
a small percentage of cases the tumour is not a GIST. In fact, the latest ESMO
recommendations [8] explicitly consider surgical
excision of tumours without prior histological confirmation of GIST if they are
larger than 2 cm or show an increase in size. Current NCCN guidelines even
regard preoperative biopsy as not appropriate in easily resectable lesions and
state that it is mandatory only if neoadjuvant treatment is planned [7]. Three of the four benign lesions
were at a size of greater than 2 cm and by this met the criteria specified in
both guidelines.Follow-up did not show any local recurrence or distant metastases, and
all patients were alive at the end of the follow-up period. This finding is
similar to results from previous studies, which yielded excellent oncological
long-term outcomes of laparoscopic resection of gastric GISTs [12, 14–16, 18–25, 32]. Median follow-up in our study was
18 months and some patients with low-risk GIST were not followed up through
standardised exams (CT and endoscopy) but only indirectly by means of phone
calls, which might not be sufficient to detect all tumour recurrences.
Therefore, our results have to be interpreted with caution and no definite
conclusions on the oncological safety of laparoscopic resection of gastric GIST
can be made at this point. Even though in our series there were no recurrences
in patients with intermediate and high risk tumours, we advocate that all
patients with resected GISTs of these risk categories are included in clinical
trials assessing the effect of adjuvant treatment [13, 39].


## 5. Conclusions

In summary, our findings support the application of laparoscopy for the
resection of localised very low, low, and intermediate risk GISTs of the
stomach. Special care needs to be employed when resecting lesions of the
posterior gastric wall, which seem to be more prone to postoperative morbidity.
The threshold to laparotomy should be rather low in case of intraoperative
difficulties, especially in obese patients if there is no special experience in
bariatric surgery. For large lesions and tumours in unfavourable locations such
as the gastroesophageal junction or small curvature, neoadjuvant imatinib
treatment might be an option to facilitate organ-preserving surgery.To allow for a definitive recommendation of laparoscopic surgery as the
new “gold standard” in the treatment of localised GISTs of the stomach, it
would be highly desirable to have results from one or several randomised
controlled trials [41]. The establishment of such trials,
however, is not easily possible. Surgical procedures which have shown good
results in nonrandomised studies and with which clinicians and patients have
had an excellent (subjective) experience are often established as clinical
standard without randomised controlled trials being conducted [42]. In our opinion, even if based only
on data from retrospective analysis, laparoscopic wedge resection should be
recommended as treatment of choice for localised GISTs of the stomach if the
named limitations and precautions are borne in mind.



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