Introduction

Indeterminate biliary duct strictures (IBDS) pose a diagnostic dilemma, and digital single-operator cholangioscopy (d-SOC) has improved diagnostic accuracy by enabling targeted intra-ductal biopsies (1-3). There is no consensus on the optimal biopsy strategy, but data suggests that at least four single biopsies yields adequate specimen samples for pathological examination (4). Considering the desmoplastic character of cholangiocarcinoma obtaining larger and deeper samples may have a higher diagnostic yield. The aim of this study was to compare the diagnostic yield of d-SOC guided single standard biopsies to those obtained via bite-on-bite-biopsy (BBB) technique in patients with IBDS.

Aims & Methods

This international, multi-center, prospective cohort study included patients with a diagnosis of IBDS who underwent d-SOC from November 2020 to August 2022 at fourteen European tertiary referral centers (Dutch Trial Register: NL9649). IBDS was defined as a bile duct stricture of indeterminate nature after previous laboratory work-up, imaging or endoscopic retrograde cholangiography with or without brush-cytology of fluoroscopy guided intra-ductal biopsies. During d-SOC, in every patient sampling of the stricture(s) was performed by firstly obtaining at least 4 single biopsies, and secondly obtaining at least 1 BBB. Definitive diagnosis was established on pathology outcomes (biopsies or surgical resection specimens) and clinical follow-up of at least one year. Primary outcome was the accuracy of both biopsy techniques.

Results

Eighty-nine patients were included (62% male, median age: 66 years), 52 of whom had a hilar and 37 a distal stricture. Single and BBB biopsies were technically successful and with sufficient tissue for diagnosis in 82 (92.1%, median number of biopsies = 4) and 78 (87.6%, median number of BBB biopsies = 2), respectively. These biopsies confirmed malignancy in 31/82 and 29/78 of cases, respectively. Comparing the two biopsy techniques, these techniques yielded different results in 4/78 patients (5.1%).
In 82 (92.1%) patients follow-up was complete and malignancy was confirmed in 51 (62.2%) patients, resulting in an overall sensitivity, specificity and accuracy of 60.8%, 100% and 75.6% of both techniques combined. For both sampling techniques, sensitivity and accuracy decreased significantly if a stent was placed at a prior ERC (n = 37, 41.6%) or whenever prior intra-ductal tissue acquisition had been performed (n = 41, 46.1%). The number of BBB did not affect sensitivity or accuracy. No adverse events related to d-SOC guided biopsies were noted.

Conclusion

In this prospective study, BBB did not outperform at least four random single biopsies of IBDS. Prior manipulation of the IBDS, by stent placement or prior tissue acquisition, is associated with a decreased yield.

References

1. Angsuwatcharakon P, Kulpatcharapong S, Moon JH, et al. Consensus guidelines on the role of cholangioscopy to diagnose indeterminate biliary stricture. HPB (Oxford). 2022;24(1):17-29.
2. Navaneethan U, Hasan MK, Lourdusamy V, et al. Single-operator cholangioscopy and targeted biopsies in the diagnosis of indeterminate biliary strictures: a systematic review. Gastrointestinal Endoscopy. 2015;82(4):608-614.e602.
3. Almadi MA, Itoi T, Moon JH, et al. Using single-operator cholangioscopy for endoscopic evaluation of indeterminate biliary strictures: results from a large multinational registry. Endoscopy. 2020;52(7):574-582.
4. Bang JY, Navaneethan U, Hasan M, et al. Optimizing Outcomes of Single-Operator Cholangioscopy–Guided Biopsies Based on a Randomized Trial. Clinical Gastroenterology and Hepatology. 2020;18(2):441-448.e441.

Disclosure

P.J.F. de Jonge is a speaker and received a consultancy fee for Boston Scientific. J.J. Vila is a speaker for Pentax, Cook Medical, and Olympus and is a consultant for Boston Scientific. M.W. James received consultancy fees from Boston Scientific and Cook Medical. K.W. Oppong received research funding for investigator initiated studies from Medtronic, and received speaker fees from Medtronic and Boston Scientific. D. Joshi is a speaker and received consultancy fees from Boston Scientific, Cook Medical, and Mirum Pharmaceuticals. M. Ellrichmann received research funding for industry initiated studies from Boston Scientific. He received research funding for investigator initiated trials from Boston Scientific, He is a consultant to Boston Scientific, Microtech, Medwork and Olympus. L. Kylänpää received a speaker fee from Boston Scientific. F. van der Heide received a speaker fee from AbbVie. P. Hindryckx is a speaker and received consultancy fees from Medtronic, Boston Scientific, Viatris, Fujifilm, and Medwork. V. Cennamo is a consultant and speaker for and received travel grants from Olympus Italia, Olympus Europe, and Euromedical. G.J.M. Webster is a consultant and speaker for Boston Scientific, Cook Medical, Pentax Medical, and Olympus Europe. M.J. Bruno received research funding for industry initiated studies from Boston Scientific and Cook Medical. He received research funding for investigator initiated studies from Boston Scientific, Cook Medical, Pentax Medical, Interscope, Mylan, and ChiRoStim. He is a consultant to Boston Scientific, Cook Medical, and Pentax Medical. The remaining authors have no conflicts of interests to disclose.

Introduction

Indeterminate biliary strictures pose a significant diagnostic challenge, as they can result from a wide spectrum of both benign and malignant conditions. Differentiating between these is crucial due to different management strategies. Conventional methods like endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology have limited sensitivity, often leading to repeated procedures and delays in treatment. Peroral cholangioscopy (POC) offers direct bile duct visualization and targeted biopsies, improving diagnostic accuracy. Modern systems, like the SpyGlass™ DS, enhance procedure feasibility and image quality.

Aims & Methods

Aims: The aim of our study is to assess the effectiveness of single-operator peroral cholangioscopy system (POCS) with its digital version SpyGlass^TM Direct Visualization System with SpyBite biopsies as a promising modality for accurate diagnosis of biliary strictures.
Method: We performed a two-center retrospective analysis of prospective database from March 2019 to March 2025. Each patient underwent peroral cholangioscopy using SpyGlass^TM Direct Visualization System with SpyBite biopsies for the diagnosis of indeterminate biliary strictures.

Results

We identified 162 patients who underwent peroral cholangioscopy during the study period (96 males and 66 females). The medium age of the patients was 63.04 years. There was 100 % technical success of the procedure. All patients underwent POCS due to indeterminate biliary strictures. Before the procedure CT scan was performed and positive for biliary stenosis in 115 (70.9%) of the cases. The biliary stenoses were located as follows: 20 (12.3%) in the distal common bile duct, 29 (17.9%) in the proximal common bile duct, 102 (62.9%) at the hepatic hilum and 11 (6.7%) in the intrahepatic bile ducts.
Benign disease was diagnosed in 39 (24.07 %) of the patients. Visual impression for malignant desease (at least one of the following- tortuous dilated vessels, friability and easily bleeding, infiltrative stricture, polipoid mass, nodular eleveted lesion, vegetative mass, fish-egg lesion, finger - like villiform lesion and irregular papillary or granular lesion) was found in 123 (75.9%) of the patients. The most reliable correlation with malignancy was found to be the presence of infiltrative strictures - 113 (69.7%) patients. A final diagnosis of cholagiocarinoma was established in 84
(51.8%) of them. In 39 (24.07%) patients, no tumor cells were found in the specimen. Visual impression accuracy with SpyGlass was 100% (with 100% sensitivity and 100% specificity). SpyBite biopsies accuracy was 69.05 % (with 68. 3% sensitivity and 100% specificity).

Conclusion

POC has proven valuable in evaluating indeterminate biliary strictures, offering advantages over ERCP by allowing real-time visualization and targeted biopsies. Our study supports POC's superior accuracy, especially in identifying malignant lesions, with visual impression achieving up to 100% sensitivity and specificity. However, POC adoption is limited by operator expertise, the need for standardized interpretation, and availability. While adverse events are rare (<10%), careful patient selection is essential. In conclusion, POC holds substantial promise as a key diagnostic tool for indeterminate biliary strictures, with ongoing improvements enhancing its clinical role.

Disclosure

No conflict of interest

Introduction

By definition, indeterminate biliary strictures are those that cannot be diagnosed with routine imaging modalities, including ultrasound, CT scan, and MRI. In such cases, single-operator cholangioscopy (SOC) has emerged as a useful tool for diagnostic and therapeutic interventions, which enables visualization of the bile duct and allows for targeted biopsies of suspicious lesions. The use of SOC has been shown to improve diagnostic accuracy, decrease the need for additional procedures, and guide therapeutic interventions. Nevertheless, pooled sensitivity for diagnosis of SOC-guided biopsies in the diagnosis of malignant biliary strictures is limited with approximately 60%. So far, there is no evidence on which biopsy technique is best and how many biopsy samples need to be taken to improve diagnostic accuracy.

Aims & Methods

Aim: To evaluate the best sampling technique comparing two versions of the SpyBite forceps to optimize diagnostic yield for the differentiation of indeterminate biliary stricture.
Patients and methods: Patients with an indeterminate biliary stricture with an independent indication to perform an ERCP with SOC and bile duct sampling were recruited to participate in this prospective, randomized, multicenter study. Patients were equally randomized into the following study arms: (i) single biopsy (SB); (ii) multiple biopsies with suction technique (MB); (iii) bite-on-bite biopsies (BB). At least 6 biopsies had to be obtained in each group. Furthermore, the best sampling technique was transferred into phase 2 of the study comparing conventional forceps (Spybite) vs. larger forceps (Spybite max.). Final diagnosis was defined as prove of malignancy, histology of surgical resectate or 6 months follow-up without signs of malignancy. Adequacy of the samples was rated according to a 6 point rating scale (cytological samples rate 0-2; histological samples rates 3-5). Sensitivity/specificity of samples were defined as primary endpoint.

Results

A total of 60 patients (20pt. per group, mean age 67y, 48% female) were included in the first study phase. In the SB, MB and BB group a mean of 6.4, 6.7 and 6.5 samples was taken, respectively. Of note, in the MB group a significant difference of the number of samples being evaluated (∆=3.5; -47.8%) was observed indicating a loss of samples during suction. Resulting sensitivity/specificity of the obtained samples was: SB 76/89%; MB 61/85%; BB 79/92%, with a significant lower level in the MB group compared to SB and BB (p=0.01). In the 2^nd study phase 20 patients were included per group. Usage of the larger forceps significantly increased sensitivity to 85% (p=0.01) with a specificity of 95% applying the BB technique. Conventional forceps obtained cytological samples in 48.3% and histological samples in 51.7%, whereas larger forceps resulted in 8.3% cytological samples (p=0.0001) and histological samples in 91.7% (p=0.001).

Conclusion

Based on the results of this study, the bite-on-bite biopsy technique using larger forceps (Spybite max.) appears to be the best sampling technique for optimizing diagnostic yield in the differentiation of indeterminate biliary stricture.

Disclosure

Mark Ellrichmann, Arne Kandulski, Markus Dollhopf, Arno Dormann, Alexander Dechene, Torsten Beyna, Christian Gerges received lectures fees from Boston Scientific

Introduction

Diagnosis of biliary obstructions is a challenge especially when histopathology is inconclusive. Indeterminate biliary strictures often require additional verification and a personalized approach.

Aims & Methods

This study investigates the prevalence, characteristics, and natural history of indeterminate biliary strictures. This retrospective study covers patients treated with ERCP because of jaundice due to biliary stricture(s) of unknown etiology. Exclusion criteria were prior liver transplantation, visible tumor, lithiasis, acute pancreatitis, PSC, or any known cause of dilated biliary ducts with subsequent biliary stricture diagnosed with imaging studies (US, CT, MRI, or EUS) and serology and clinical data. A diagnosis of potentially benign biliary stricture was based on cytology/histopathology evaluation of samples taken on primary ERCP. The study participants were monitored every 2–3 months with further endoscopic, imaging, and serological evaluations as needed.

Results

A total of 510 patients were treated with primary ERCP for biliary obstruction of indeterminate etiology. The 186 (36.5%) had biliary strictures with negative cytology/histopathology (category II per Papanicolaou guidelines), of these 55 (29.6%) had strictures in the liver hilum, 22 (11.8%) in the common bile duct (CBD), and 108 (58.1%) in the intrapancreatic region. Malignancy was confirmed in subsequent tests in 40 patients (21.5%). A benign cause was diagnosed in 77 cases (41.4%), including pancreatitis, PSC, ischemia, IgG4-SC, and Mirizzi syndrome, while 69 strictures (37.1%) remained indeterminate. Strictures in the liver hilum had a higher rate of eventual malignancy (30%) compared to CBD (23%) and intrapancreatic (16%) localization. Lithiasis was more common in intrapancreatic strictures (12%), while PSC was more frequent in hilar strictures (14%). During 6-month follow-up of the 69 indeterminate cases: 17 patients received a diagnosis (8 lithiasis, 5 malignancies, 2 chronic pancreatitis, 1 benign neoplasm, 1 IgG4-SC), 4 patients died from unrelated causes, 48 cases (25.8% of the potentially benign stricture group) remained indeterminate.

Conclusion

A quarter of benign biliary strictures remain indeterminate in 6 months follow-up, while 20% of patients with indeterminate receive diagnosis of malignancy.

Introduction

Despite the advancements in imaging modalities, diagnosis of biliary strictures remains challenging in some cases. Endoscopic retrograde cholangiopancreatography (ERCP) is the current gold standard for diagnosis. However, the pathological diagnosis via ERCP is limited due to the small specimen. Therefore, a novel device for the diagnosis of biliary stricture has been long-awaited. Although high sensitivity and specificity have been reported for probe-based confocal laser endomicroscopy (pCLE) for the diagnosis of biliary strictures using the Miami Classification, it remains uncertain whether confocal miniprobes can be properly applied to the target site with the use of pCLE under fluoroscopic guidance. The aim of the present study was to prospectively evaluate the clinical utility of pCLE under the direct view of peroral cholangioscopy (POCS) for the diagnosis of biliary strictures.

Aims & Methods

Consecutive patients with biliary strictures were included. All patients underwent imaging examination, such as computed tomography, magnetic resonance imaging, or endoscopic ultrasound, and were found to have biliary disorders. We investigated sensitivity, specificity, and accuracy to diagnose malignancy for: 1) ERCP alone, 2) POCS, 3) pCLE under the direct view of POCS, and 4) tissue sampling under the direct view of POCS. pCLE images were interpreted prospectively using the Miami Classification. We also evaluated other outcomes of pCLE under the direct view of POCS.

Results

A total of 30 patients (17 with malignant lesions) were prospectively enrolled.
1) ERCP alone showed 88.2% sensitive, 46.2% specific, and 70% (95% confidence interval [CI], 52.1%–83.3%) accurate.
2) POCS showed 100% sensitive, 76.9% specific, and 90% (95% CI, 74.4%–96.5%) accurate.
3) pCLE under the direct view of POCS showed 94.1% sensitive, 92.3% specific, and 93.3% (95% CI, 78.7%–98.8%) accurate.
4) Tissue sampling under the direct view of POCS showed 82.4% sensitive, 100% specific, and 90% (95% CI, 74.4%–96.5%) accurate.
The POCS could not pass the biliary stricture in four patients, and we could not complete successful observation of the target area. Therefore, the success rate of pCLE under the direct view of POCS was 88.2% (30/34). The median procedural time for pCLE under the direct view of POCS was 42 min (interquartile range [IQR], 31.3–48 min). Accurate diagnosis rate of common bile duct and accurate diagnosis rate of hilar and intrahepatic bile duct were 86.7% (13/15), 100% (15/15) respectively. There was no significant difference among stricture locations (P=0.48). Adverse events occurred in three patients (one with mild pancreatitis, and two with mild cholangitis).

Conclusion

pCLE under the direct view of POCS provided highly accurate and sensitive characterization of biliary strictures and showed the potential for more diagnostic reliability and reduction of delays in diagnosis.

Clinical Case Summary

A 59-year-old man was admitted with painless jaundice. Laboratory data revealed elevated liver enzymes and hyperbilirubinemia (ALT 95UI/L, AST 54UI/L, ALP 550UI/L, total bilirubin 6mg/dL and direct bilirubin 4.6mg/dL). CT confirmed an unresectable 4cm perihilar infiltrative lesion with extensive portal vein invasion and cavernous transformation. An US-guided biopsy of the lesion followed by percutaneous transhepatic cholangiography were performed, allowing palliative biliary drainage with non-covered metal stents. Nevertheless, biopsy sample histopathology yielded no intersected neoplastic tissue.
Given the strong suspicion of malignancy and the need for histopathology to guide systemic treatment, endoscopic retrograde cholangiopancreatography (ERCP) with cholangioscopy-guided biopsies was proposed. The procedure started by conventional biliary cannulation. Cholangiography revealed the metallic stents in situ crossing the hilum. Biliary endoscopic sphincterotomy was performed and a 3.2mm cholangioscope (EyeMAX™) was successfully introduced. The common bile duct and the hepatic ducts were carefully explored advancing the cholangioscope through the stents into the intrahepatic ducts. Detailed inspection of the biliary mucosa identified areas of pseudopolypoid appearance covering the stent body in the hilar region with marked friability and aberrant vascularization. Cholangioscopy-guided biopsies were laboriously performed through the mesh of the metal stents using a 1mm biopsy forceps (EyeMAX™ biopsy forceps). No displacement or damage to the stents were observed. Histology confirmed a moderately differentiated cholangiocarcinoma, and palliative chemotherapy could be started.
Biliary non-covered metal stents should only be used after a definite histologic diagnosis of cancer is stablished. Despite the potential technical limitations of this unreported approach, targeted biopsies through the mesh of metallic stents seem effective without compromising stent integrity.

References

Cholangioscopy images.
Fluoroscopy images.
Histopathology images.