Robotic Duodenal Sleeve Resection for Gastrointestinal Stromal Tumor with Rare Exon 8 KIT Mutation Following Neoadjuvant Imatinib

Summary

This video case report demonstrates the unique management of a duodenal gastrointestinal stromal tumor with a rare, understudied, exon 8 KIT mutation. Neoadjuvant therapy resulted in a 30% reduction in tumor size, making the patient a candidate for a robotic-assisted duodenal sleeve resection instead of the more morbid pancreaticoduodenectomy.

Abstract

Gastrointestinal stromal tumors (GISTs) predominantly arise in gastric tissue, with only 5% occurring in the duodenum. While surgery remains the cornerstone of treatment, patients with large tumors or a high risk of recurrence may benefit from targeted therapy. Most GISTs harbor mutations in the KIT receptor tyrosine kinase, making them potentially responsive to tyrosine kinase inhibitors (TKIs) such as imatinib. Mutations in exons 9, 11, 13, and 17 are most common and are therefore included in most genetic panels. However, up to 15% of patients lack mutations in these exons and demonstrate variable responses to TKIs.

This video demonstrates the management of a duodenal GIST located near the ampulla. Given the tumor's size and location, pancreaticoduodenectomy (PD) would likely be required for resection. Genetic testing was performed to assess the potential for targeted therapy to reduce tumor burden and allow for a more limited resection. Although no mutations were identified in exons 9, 11, 13, or 17, additional testing revealed a rare exon 8 KIT mutation. Exon 8 mutations have been reported in hematopoietic malignancies but are rarely described in GISTs, and their sensitivity to TKIs remains unclear. After informed consent, imatinib was initiated, resulting in a 30% reduction in tumor size at 6 months. The patient subsequently underwent a robotic duodenal sleeve resection with lateral duodenojejunostomy. His postoperative course was uncomplicated, and he was discharged on postoperative day 5. The patient received adjuvant imatinib and remains recurrence-free at three years.

Given the rarity of exon 8 KIT mutations in GISTs, this mutation is not included in standard genetic panels. Although further study is needed, this case suggests that exon 8-mutant GISTs may respond to TKIs, potentially enabling less extensive surgical resection.

Introduction

Gastrointestinal stromal tumors (GISTs) can be found throughout the entire gastrointestinal tract but are most common in the stomach (60%) and small intestine (30%). Only 5% of tumors present in the duodenum, which can be a challenging location for surgical resection^1,2. Although surgery continues to be the primary modality of GIST treatment, targeted systemic therapies, such as tyrosine kinase inhibitors (TKIs), can be considered for patients with high tumor burden or increased risk of recurrence. Key pathological factors in prognostication and risk stratification include tumor size, mitotic rate, and, more recently, tumor location has been implicated, where gastric tumors tend to be more indolent and intestinal tumors more aggressive^3,4.

The majority of GISTs have a mutation in the KIT receptor tyrosine kinase or platelet-derived growth factor receptor alpha (PDGFRA). However, up to 15% lack a mutation in the commonly tested KIT exons 9, 11, 13, and 17 or PDGFRA exons 12, 14, 18^5,6. Evaluating tumor mutational status can have a significant impact on management and clinical outcomes. These include confirmation of diagnosis and prognostication if other studies are inconclusive, as well as predicting responsiveness to targeted systemic therapies². Tumors lacking these well-described mutations are typically defined as 'wild-type GISTs' and generally considered to have little to no response to TKI therapy⁶. This GIST subset, however, is likely an oversimplification, as tumors may be more genetically heterogeneous than previously thought. Recent reports have challenged this notion, demonstrating that wild-type GISTs with an activating exon 8 mutation have an in vitro response to imatinib, and patients with this mutation may benefit from imatinib administration^7,8,9.

For optimal oncologic outcomes of any GIST, an R0 resection without lymph node clearance remains the goal. However, the unique anatomy of the duodenum and close proximity to several critical structures, such as the pancreas, biliary ducts, and ampulla of Vater, may pose a significant challenge for managing duodenal GISTs^10,11. Broadly, options for resection include a limited duodenal resection or a more extensive PD. Factors contributing to this decision include tumor size, proximity to the ampulla, and risk of tumor rupture. Another important consideration in performing an oncologic resection is minimizing post-operative surgical morbidity, which could impact resumption of systemic therapy, if indicated. Thus, the surgical procedure of choice is not standardized for duodenal GISTs and remains highly individualized^10,11.

CASE PRESENTATION:

A 73-year-old male with an unremarkable past medical and surgical history presented with symptomatic anemia for which he underwent an esophagogastroduodenoscopy (EGD) and colonoscopy at an outside facility. No abnormalities were found on colonoscopy, but a large, ulcerated mass was identified near the ampulla of Vater during the EGD. Biopsies were obtained but were negative for malignancy. He was then transferred to our facility for additional care.

Diagnosis, Assessment, and Plan:

A repeat EGD along with endoscopic ultrasound was performed, showing a hypoechoic, lobulated mass with overlying ulceration (Figure 1). The mass appeared to be originating from the muscularis propria and was opposite and 1cm distal to the ampulla of Vater. A fine needle aspiration (FNA) biopsy was performed, revealing strong positivity for KIT (CD117) and DOG1, markers of GISTs, on immunohistochemical staining. Unfortunately, a mitotic count could not be obtained due to scant sampling. Staging computed tomography (CT) showed the disease was isolated to the duodenum with the mass measuring 4.7 x 3.3 x 2.9 cm (Figure 2).

Due to the size and location of the mass, a PD was likely necessary if surgical resection had been pursued at time of presentation For this reason, genetic testing was obtained to evaluate the potential for targeted therapy to reduce the tumor burden, potentially allowing for a more limited resection. Initial genetic testing was negative, but further testing revealed a rare exon 8 KIT mutation. Following consultation with the patient, neoadjuvant therapy with imatinib was started at a daily dose of 400 mg to facilitate a more conservative surgical approach. Imaging performed at 3 and 6 months demonstrated tumor size decreases of 18% and 30%, respectively. In light of this response, surgical management was subsequently pursued.

Protocol

1. Patient positioning and placement of robotic ports

1. The patient was placed in a supine position on a split-leg table with arms out. After sterile preparation, the patient was draped in standard fashion.
2. An optical separator device was inserted through a left upper quadrant incision. CO₂ insufflation was carried out after entry into the peritoneal cavity.
3. The peritoneal lining and surface of visceral organs were carefully inspected to evaluate for metastatic disease that would alter intended operative management.
4. Four robotic ports were positioned in the upper abdomen, and two assistant ports were placed inferiorly (Figure 3). The 12-mm port located in the left lower quadrant was assigned for stapler introduction.
5. Once port placement was completed, the patient was placed in the reverse Trendelenburg position, after which the robotic system was docked.

2. Entry into the lesser sac and Kocherization of the duodenum

1. Cranial retraction of the liver was achieved using a flexible right flank liver retractor.
2. Access to the lesser sac was obtained with a bipolar electrocautery device along the stomach's greater curvature, while carefully preserving the gastroepiploic vessels.
3. A mobilization of the hepatic flexure of the right colon was performed, as well as a wide Kocher maneuver to mobilize the duodenum.

3. Mobilization of GIST and jejunum

1. In our case, the duodenal mass was visualized in the 3^rd portion of the duodenum
   NOTE: It was noted to be invading the transverse colon mesentery.
2. Dissection of the mass away from the retroperitoneum ensued. Involvement of the transverse colon mesentery required further dissection to medialize (Figure 4).
3. The ligament of Treitz was identified and divided from the patient's right using electrocautery. The jejunum was mobilized into the patient's right upper quadrant.
4. A mesenteric window was opened with a bipolar electrocautery device. The proximal jejunum was transected using a 60-mm purple Endo GIA stapler cartridge. The jejunal mesentery was then further dissected up to the level of the pancreas.

4. Resection of GIST and removal of specimen

1. Duodenal mobilization was completed, allowing for resection of the devascularized duodenum and mass using an additional 60 mm purple staple load.
2. The specimen was placed into a 15 mm endoscopic bag. The supraumbilical port site incision was extended to allow extraction. The specimen was oriented extracorporeally and taken to pathology for evaluation.
3. A sealant gel port was placed in the extended extraction site, and the abdomen was re-insufflated.

5. Cholecystectomy and creation of duodenojejunal anastomosis

1. A top-down cholecystectomy was performed: hook electrocautery was used to mobilize the gallbladder from the liver bed and clear all surrounding tissue until identification of two structures entering the gallbladder ("the critical view of safety"). The cystic artery was clipped and then divided with a bipolar cautery device.
2. A transverse incision was made across the cystic duct using robotic scissors.
3. A Fogarty catheter was passed into the duodenum via the transected cystic duct to confirm intact ampulla of Vater.
4. An enterotomy was created in the mesenteric portion of the duodenum and another in the jejunum. A side-to-side stapled duodenojejunostomy was performed using a 60 mm purple load on an Endo GIA stapler.
5. Here, the Fogarty catheter was visualized directly passing through the ampulla of Vater into the neo-duodenal lumen via common enterotomy.
6. Once intact biliary anatomy had been confirmed, the Fogarty catheter was removed and cholecystectomy completed: two endoscopic clips were placed on the proximal cystic duct and one clip distal to the transverse incision. Transection of the duct between clips was completed.
7. The common enterotomy was closed in two layers: 3-0 V-Loc running suture on the inner layer and 3-0 silk Lembert sutures to imbricate enterotomy suture line.
8. The duodenal staple line was imbricated using 3-0 silk Lembert sutures.

6. Drain placement and abdominal closure

1. The abdomen was thoroughly irrigated with multiple liters of saline and inspected to ensure adequate hemostasis.
2. A single 19-French Blake drain was positioned in the right upper quadrant, coursing posterior to the duodenojejunostomy.
3. The robot was undocked at that time. A laparoscopic port-site closure device was utilized to secure the 12-mm left lower quadrant port using a #1 Vicryl figure-of-eight suture, followed by abdominal desufflation.
4. The extended midline specimen-extraction site was closed with #1 PDS figure-of-eight sutures.
5. The skin and subcutaneous layers were irrigated and subsequently closed using 4-0 Monocryl sutures.

Results

The patient had an unremarkable recovery in the immediate post-operative period. He was admitted to the surgical floor with a nasogastric tube in place for gastric decompression due to the newly created duodenojejunal anastomosis. This tube was removed on postoperative day one, and he tolerated a clear liquid diet, which was subsequently advanced to a regular diet on postoperative day three. His surgical drain output remained low in volume and serosanguinous in quality; it was ultimately removed on post-operative day fou...

Discussion

Here, we present the unique management of a patient with a duodenal GIST in close proximity to the ampulla. At presentation, the mass was potentially resectable but would have likely required a multivisceral resection with PD rather than a more limited duodenal sleeve resection. Further, typical prognostication and risk stratification was unsuccessful given the inability to determine a mitotic index on biopsy pathology and standard genetics panel, yielding negative results. Additional testing revealed a rare exon 8 KIT m...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
#1 Vicryl Suture	Medtronic	CL-64-M
0 Vicryl Ties	Ethicon	J646H
2-0 Silk Suture - Cut to 8"	Ethicon	K833-H
3-0 V-LOC V-20 6" x 3	Covidien	VLOCM0604
4-0 Monocryl	Ethicon	Y496G
4-0 Prolene on RB 1	Ethicon	8557H
4-0 V-Loc CV-23 6" x 2	Covidien	VLOCM0024
5-0 Polydioxanone RB-2 Cut to 5"	Ethicon	Z148-H
Banded bag 28" x 36"	McKesson	13628	Cover non-sterile equipment in sterle field
BD ChloraPrep Hi-Lite Orange 26-mL applicator with sterile solution	BD (Becton, Dickinsone and Company)	930815	Sterile Chlorhexidine preparation
Bladeless optical trocar, 5 mm size, 100 mm length	Covidien	ONB5STF
Bladeless Trocar, 12 mm size, 100 mm length	Covidien	NONB12STF
Bladeless Trocar, 15 mm size, 100 mm length	Covidien	NB15STF
Bladeless Trocar, 5 mm size, 100 mm length	Covidien	NONB5STF
BLAKE Silicone Drain, Size 19 Fr, Round	Ethicon	2232	Abdominal drain
Cadiere	Intuitive Surgical	471049
Clean and protect laparoscope lense	McKesson	21345
Coaxial umbilical cable	Medtronic	203CXC
Da Vinci XI Arm Drape	Intuitive Surgical	470015	Sterile drape for robotic arms
Da Vinci XI Column Drape	Intuitive Surgical	470341	Sterile drape for bedside robot
Da Vinci XI Universal Seal 5-12 mm	Intuitive Surgical	470500	Robotic Trocar seal
Endo catch gold single-use specimen pouch	Covidien	173050G	Laparoscopic specimen pouch
Endo Floating Ball Electrodes	Medtronic	122011	Monopolar electrocautery device
Endo GIA Ultra Universal Stapler	Covidien	EGIAUXL	Laparoscopic stapler
Endoscopic surgery swab	Covidien	173019	Swab fluid and assist with blunt dissection
Exofin Skin Adhesive	McKesson	EX71010	Skin glue
Fenestrated Bipolar	Intuitive Surgical	471205
First Entry Access System, 5 x 100 mm	Applied Medical	CTF03
Garment compress Medium, Calf	Zimmer Biomet	VG501M	Sequential compression device applied to calves for deep venous thrombosis prophylaxis
Gelpoint Retracter Sleeve introducer	Applied Medical	CNGL2
Gelseal alexis mini Sleeve 10 mm, 12 mm	Applied Medical	CNGL3
Hook electrocautery	Intuitive Surgical	470183
Jackson-Pratt bulb reservoir 100 cc	McKesson	SU1301305	Drainage suction bulb reservoir
Laparoscopic Blade Electrode, 6.5"	Coviden	E14506	Laparoscopic electrocautery blade
Laparoscopic Clip applier 10 mm	Covidien	176657	Laparoscopic clip applier
Laparoscopic Clip applier 5 mm	Covidien	176630	Laparoscopic clip applier
Laparoscopic electrode Flat L-hook	Covidien	E3774-36C	Laparoscopic electrocautery hook
Laparoscopic sealer/divider, Maryland, curved Jaw	Covidien	LF1944
Laparotomy sponge, 4" x 18", X-ray and RF-Detectable	Medtronic	L041804P01C1
Large needle driver	Intuitive Surgical	471006
Large SutureCut needle driver	Intuitive Surgical	471296
Maryland Bipolar	Intuitive Surgical	471172
Monopolar Curved scissor tip cover accessory	Intuitive Surgical	400180
Monopolar curved scissors	Intuitive Surgical	470179
Optical Obturator, 8mm, bladeless	Intuitive Surgical	470359	Obturator for placement of robotic trocar
OR Fluid warming drape	Medline	SDREC44
Pneumoclear smoke evacuation tube set	STRYKER	620050350	Smoke evacuator tubing
Prograsp	Intuitive Surgical	471093
Skin Stapler	Covidien	8886803712	Skin stapler
Small grasping forcep	Intuitive Surgical	471400
Smoke MGMT EXTD Nozzle for 4 in electrode	Medtronic	VSMEN4	Electrocautery pencil with smoke evacuation
Smoke pencil with edge electrode 10 Ft	Medtronic	VSMP10	Electrode for electrocautery
Stapler reload, 60 mm, reinforced	Covidien	SIGTRSB60AXT
Step insufflation/access needle, 100 mm	Covidien	S100000	Laparoscopic blunt tip access needle
Sterile surgical Leggings 31" W X 48" L	McKesson	89408
Sterile table Drape, 4'	Grayline Medical	418HDS
Suction irrigation system, battery operated	McKesson	250070520
Suction tube handle, Bulb tip Yankauer	McKesson	K86	Yankauer Suction handle
Suction Tubing 20FT, 9/32 inch	McKesson	N720A	Suction tubing
Surgical Gown	McKesson	41734
Surgical utility drape with tape	Medline	DYNJP2405	Drapes for sterild field
SURGICEL Absorbable Hemostat	Ethicon	1952S	Hemostatic cellulose
Tip up Grasper	Intuitive Surgical	471344
Umbilical tape	Ethicon	W276
Vessel Loop Silicone	McKesson	31145660	Vessel loop for retraction of vascular, pancreatic neck
Vessel sealer extend	Intuitive Surgical	480422