Peroral cholecystoscopy–guided interventions through a lumen-apposing metal stent after EUS-guided gallbladder drainage: proof-of-concept study in a swine model

Abstract

Background and Aims

EUS-guided gallbladder drainage (EUS-GBD) using a lumen-apposing metal stent (LAMS), originally developed as drainage for cholecystitis, enables endoscopic access into the gallbladder lumen. However, few studies have investigated the feasibility of peroral cholecystoscopy (POCCS)-guided interventions through a LAMS.

Methods

EUS-GBD using a LAMS followed by POCCS-guided interventions were performed in 4 swine. Technical success, safety, and feasibility of POCCS visualization and POCCS-guided biopsy sampling and mucosal resection through the LAMS immediately and 3 weeks after EUS-GBD were investigated. Additionally, all specimens including necropsy were pathologically evaluated.

Results

POCCS and target biopsy sampling were successful through the LAMS in all swine immediately after EUS-GBD, without any adverse events. POCCS-guided biopsy sampling and mucosal resection 3 weeks after EUS-GBD were technically feasible and pathologically assessable in all swine. The necropsy specimens displayed hyperplastic and inflammatory changes in the gallbladder and nearby organs after 3 weeks of EUS-GBD.

Conclusions

POCCS-guided interventions including mucosal resection were technically feasible through a LAMS after EUS-GBD.

Because of the difficulty in diagnosing gallbladder neoplasms through imaging, cholecystectomy can be performed as a diagnostic treatment.^1,2 However, this approach may occasionally lead to unnecessary surgery, carrying the risk of potential adverse events (AEs) such as biliary and vascular injuries.³ Furthermore, a pathologic examination after cholecystectomy may reveal incidental malignancies, necessitating additional laparotomy for lymphadenectomy.⁴ Therefore, less-invasive diagnostic and therapeutic approaches are urgently needed to improve the clinical management for gallbladder neoplasms.

EUS-guided gallbladder drainage (EUS-GBD) using lumen-apposing metal stents (LAMSs) has emerged as an alternative for acute cholecystitis in patients unfit for emergent cholecystectomy.5, 6, 7 Given the substantial diameter of the LAMS, EUS-GBD can offer effective drainage and potentially enable transmural access to the gallbladder, facilitating subsequent endoscopic interventions.8, 9, 10 Hence, we conducted this study to explore the potential of peroral cholecystoscopy (POCCS)-guided interventions through a LAMS in a swine model.

Methods

This is a proof-of-concept study to investigate the feasibility of POCCS-guided interventions through LAMSs after EUS-GBD in a swine model. The study was carried out at the Institute for Advancing Science, Boston Scientific Corporation in Japan, with approval from the Animal Ethics Committee of the institute (approval no. S23-077).

Endoscopic procedures

Two endoscopic procedures were performed with a 3-week interval in 4 swine. The index procedure included EUS-GBD using an electrocautery-enhanced LAMS delivery system (Hot-Axios; Boston Scientific, Marlborough, Mass, USA), followed by POCCS through the LAMS, mucosal biopsy sampling, and cholecystography. EUS-GBD was carried out using a linear echoendoscope (EG-580 UT; Fujifilm Corp, Tokyo, Japan) with a dedicated US processor (SU-1; Fujifilm Corp), and POCCS was performed using a cholangioscope (Spyglass DS, 3.6 mm diameter; Boston Scientific) and gastroscopes (EG-530NW, 5.9 mm diameter [Fujifilm Corp], and GIF-H290T, 9.9 mm diameter [Olympus Medical Systems, Tokyo, Japan]). Dilation of the LAMS using a balloon catheter (Hurricane RX Biliary Balloon Dilatation Catheter; Boston Scientific) was performed to achieve scope insertion, if necessary. POCCS-guided biopsy sampling was performed using pediatric biopsy forceps (Radial Jaw 4P; Boston Scientific) through the gastroscope, and cholecystography was performed to assess bile leakage.

In the second procedure, POCCS-guided mucosal resection of the gallbladder was performed through the LAMS using a gastroscope (GIF-H290T, Olympus Medical Systems). After the local injection of sodium hyaluronate solution (MucoUP; Boston Scientific), mucosal resection was carried out using a hybrid EMR technique, consisting of a circumferential incision by a hook knife (ORISE ProKnife; Boston Scientific) followed by snaring with a standard loop snare (Captivator; Boston Scientific).¹¹ Subsequently, the LAMS was removed using alligator forceps (Rescue forceps; Boston Scientific), and cholecystography was performed to assess bile leakage. At the end of the procedure, all swine were killed, and the gallbladder as well as nearby tissues and organs were resected for pathologic evaluation. All specimens were evaluated by an independent pathologist.

Outcomes and definitions

The primary outcome was technical success of POCCS-guided mucosal resection of the gallbladder through the LAMS after EUS-GBD. It was defined as successful mucosal resection to obtain specimens assessable for pathologic diagnosis. Secondary outcomes were successful endoscopic interventions including EUS-GBD, POCCS-guided mucosal visualization, mucosal biopsy sampling and cholecystography, and procedure-related AEs.

Results

EUS-GBD and diagnostic POCCS

The baseline characteristics and details of the index procedure are shown in Tables 1 and 2 and Figure 1. After successful EUS-GBD, the digital cholangioscope was inserted into the gallbladder without balloon dilation, regardless of the diameter of the LAMS. Complete endoscopic examination of the gallbladder from the cystic duct orifice to the fundus was achieved by the cholangioscope in all swine. Meanwhile, balloon dilation of the LAMS was required to insert ultraslim and regular gastroscopes into the gallbladder, and gallbladder mucosa was visualized. However, visualization was limited because of the limited cholangioscope manipulation within the gallbladder. POCCS-guided mucosal biopsy sampling was performed under direct visualization. Cholecystography after the POCCS revealed no signs of bile leakage, and there were no AEs during and after the index procedure until the second procedure.

Table 1.

Baseline characteristics

Case no.	Sex	At index procedure			At second procedure
		Age (wk)	Size of gallbladder (mm)	Body weight (kg)	Size of gallbladder (mm)	Body weight (kg)
1	Female	14	33.6 × 23.9	37	31.4 × 20.5	43
2	Female	13	57.8 × 25.6	36	54.2 × 23.6	42
3	Female	14	33.2 × 30.8	36	31.2 × 30.3	43
4	Female	14	46.3 × 27.4	39	43.3 × 24.4	44

Table 2.

Index procedure

Case no.	EUS-guided gallbladder drainage	Puncture site	Stent			Peroral cholecystoscopy			Biopsy sampling	Cholecystography	Adverse events
			Device	Diameter (mm)	Length (mm)	Cholangioscope	Nasal scope	Esophagogastroduodenal scope
1	Success	Stomach	LAMS	15	10	Success w/o BD	Failure w/o BD	NE	Success	No leakage	None
2	Success	Duodenum	LAMS	20	10	Success w/o BD	Failure w/o BD	NE	Success	No leakage	None
3	Success	Stomach	LAMS	15	10	Success w/o BD	Success after BD	Success after BD	Success	No leakage	None
4	Success	Duodenum	LAMS	20	10	Success w/o BD	Success after BD	Success after BD	Success	No leakage	None

See the text for equipment used in this study. LAMS, Lumen-apposing metal stent; BD, balloon dilation; w/o, without; NE, not evaluated.

Figure 1.

Peroral cholecystoscopy through a lumen-apposing metal stent (LAMS) immediately after EUS-guided gallbladder drainage in the index procedure. A, Endoscopic image of insertion of the cholangioscope (Spyglass DS; Boston Scientific, Marlborough, Mass, USA) into the gallbladder through the LAMS. B, Fluoroscopic image of insertion of the cholangioscope (Spyglass DS) into the gallbladder through the LAMS. C, Fluoroscopic image of insertion of the esophagogastroduodenoscope (GIF-H290T; Olympus Medical Systems, Tokyo, Japan) into the gallbladder after balloon dilation of the LAMS. D, Peroral cholecystoscopic image of the cystic duct orifice using the cholangioscope (Spyglass DS). E, Peroral cholecystoscopic white-light image of the body of the gallbladder under narrow-band imaging. F, Peroral cholecystoscopic narrow-band image of the body of the gallbladder.

POCCS-guided interventions

Details of the second procedure are shown in Table 3. In the second procedure, all LAMSs were patent, allowing gastroscope insertion into the gallbladder without balloon dilation. As shown in Figure 2, although perforation during the circumferential incision occurred in 1 swine, a hybrid EMR was successful in all swine from the corpus of the gallbladder, with a median procedure time of 25 minutes (range, 17-40). After successful removal of the LAMS, subsequent cholecystography revealed no signs of leakage, indicating maturation of the anastomosis.

Table 3.

Second procedure

Case no.	Stent	Peroral cholecystoscopy–guided mucosal resection						Lumen-apposing metal stent removal	Anastomosis formation
		Esophagogastroduodenal scope insertion	Resection site	Mucosal resection	Sample size (mm)	Pathologic assessment	Adverse events
1	Patent	Success w/o BD	Body, hepatic side	Success	3 × 5	Assessable	None	Success	Matured
2	Patent	Success w/o BD	Body, hepatic side	Success	5 × 7	Assessable	None	Success	Matured
3	Patent	Success w/o BD	Body, hepatic side	Success	5 × 9	Assessable	None	Success	Matured
4	Patent	Success w/o BD	Body, hepatic side	Success	4 × 7	Assessable	Gallbladder perforation	Success	Matured

See the text for equipment used in this study.

BD, Balloon dilation; w/o, without.

Figure 2.

Peroral cholecystoscopy–guided mucosal resection. A, Circumferential incision using a hook knife (ORISE ProKnife; Boston Scientific). B, Hybrid mucosal resection using a standard loop snare (Captivator; Boston Scientific). C, Macroscopic image of the mucosal resection site after necropsy. D, A mucosal resection specimen of the gallbladder. E, Microscopic findings of the mucosal resection specimen of the gallbladder (H&E, orig. mag.×20).

Pathologic findings of the resected specimens

All biopsy samples and mucosal resection specimens were pathologically assessable, revealing acute inflammation in the mucosal layer. The necropsy specimens displayed extensive erosions in the mucosal layer and inflammatory cell infiltration particularly in the proper muscular layer, indicative of purulent cholecystitis. The anastomosis between the gallbladder and stomach/duodenum exhibited hyperplastic changes of the epithelium and collagenous fiber growth in the proper muscular and subserosal layers (Fig. 3).

Figure 3.

Macroscopic and microscopic findings of the necropsy specimen. A, Matured anastomosis between the gallbladder and duodenum. B, Macroscopic findings of the duodenal side of the matured anastomosis after stent removal. C, Microscopic findings of the anastomosis between the gallbladder and duodenum (H&E, orig. mag.×2).

Discussion

This study demonstrated the feasibility of POCCS and POCCS-guided interventions including biopsy sampling and mucosal resection through a LAMS after EUS-GBD in a swine model. Furthermore, all specimens obtained by the above-mentioned procedures were pathologically assessable without leakage at the anastomosis by EUS-GBD, suggesting potential application of POCCS-guided interventions for gallbladder lesions.

POCCS-guided interventions such as stone removal and polypectomy have been reported in a few case series both in animal and human studies.12, 13, 14, 15 However, the optimal timing for POCCS-guided interventions after EUS-GBD remains unclear. Immediate POCCS-guided interventions after EUS-GBD can pose a risk for bile leakage or perforation because of balloon dilation of the immature anastomosis. On the other hand, a delayed POCCS-guided intervention after the maturation of the anastomosis may carry a risk of gallbladder atrophy, leading to difficulty in subsequent interventions¹⁶ and the additional risk of delayed management. In this study, immediate POCCS-guided interventions were technically successful without any increased risk of AEs including bile leakage. Therefore, POCCS-guided interventions can potentially be performed in the same session as EUS-GBD, particularly in cases with suspected malignancy where early treatment and accurate pathologic evaluation are mandatory.

This study also showed the possibility and limitation of gallbladder mucosa visualization from the orifice of the cystic duct to the fundus by POCCS through the EUS-GBD anastomosis. Although the cholangioscope allowed visualization of most gallbladder mucosa, the duodenal side was not visualized because of the failed retroflex position within the gallbladder. Furthermore, only the limited area of the gallbladder was visualized by gastroscopes because of its limited maneuverability within the gallbladder through the LAMS. This limitation hinders POCCS-guided endotherapy such as mucosal resection on the duodenal side of the gallbladder. The use of a multibending scope or a combination of an ultrathin endoscope and dedicated devices might offer a potential solution to access to the duodenal side.^13,17

EUS-GBD using a LAMS has been reported in cases with acute cholecystitis, with AE rates of 13% to 19% including bleeding, bile leak, stent migration or blockage, and bowel perforation.18, 19, 20 In our animal study, we did not encounter those clinically overt AEs, probably because of the lack of inflammation or infection at the time of EUS-GBD. However, safety of EUS-GBD in this context needs further evaluation in human studies. EUS-guided through-the-needle biopsy sampling for pancreatic cysts has gained popularity as a diagnostic modality, with some concern for increased AEs.^21,22 EUS-guided through-the-needle biopsy sampling can be an option for a diagnostic modality for gallbladder epithelial lesions, but there is a risk of bile leakage or hemobilia. It should be clarified whether bile leakage can be prevented by aspiration of the bile within the gallbladder after puncturing by a 19-gauge needle in cases without acute cholecystitis. Because the use of cautery-enhanced LAMSs minimizes the risk of bile leakage, our POCCS-guided intervention through the LAMS, which allows diagnostic and therapeutic procedures, has advantages over EUS-guided through-the-needle biopsy sampling as a diagnostic modality for gallbladder lesions.

Our study had several limitations. First, this was a feasibility study with a small number of animals and with a short follow-up period. Before its clinical application, appropriate indications for POCCS-guided interventions should be explored. Second, a LAMS for EUS-GBD is still an off-label use in most countries. Comparison with upfront surgical cholecystectomy is mandatory in terms of safety and cost-effectiveness, but endoscopic interventions are still less invasive and might be selected in surgically unfit patients. In conclusion, POCCS and its guided interventions through LAMSs are feasible after EUS-GBD, suggesting its potential clinical application.

Disclosure

The following authors disclosed financial relationships: Y. Nakai: Research support from Boston Scientific Japan and Fujifilm Corporation; speaker for Olympus, Boston Scientific Japan, and Gadelius Medical. M. Fujishiro: Research support from and speaker for Olympus Corporation and Fujifilm Corporation. All other authors disclosed no financial relationships. Research support for this study was provided to N. Takahara and Y. Nakai by Boston Scientific Japan.