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Cholangioscopy and pancreatoscopy
Author’s Accepted Manuscript Cholangioscopy and Pancreatoscopy Amrita Sethi, Raj Shah
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To appear in: Techniques in Gastrointestinal Endoscopy Cite this article as: Amrita Sethi and Raj Shah, Cholangioscopy and P a nc r e a t o s c o p y, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2017.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cholangioscopy and Pancreatoscopy
Corresponding author: Amrita Sethi 168 Fort Washington Ave, Suite 852 New York New York, New York 10023 UNITED STATES 212-305-1909 Email: [email protected] Raj Shah Email: [email protected]
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Abstract Cholangiopancreatoscopy has evolved significantly since its introduction over 40 years ago. The systems have gone through multiple iterations that has allowed for widespread performance of per-oral cholangiopancreatoscopy (POCP) for diagnostic and therapeutic intent. Development of imaging criteria is evolving and its yield in the detection of neoplasia in conjunction with targeted tissue sampling is excellent. However, image interpretation remains a challenge. Guidelines for training in POCP, as well as demonstration of competency, are currently lacking but require deliberate debate as the technology continues to gather enthusiasm and momentum as an established complement to ERCP.
1-Introduction For endoscopists, the natural inclination is to have direct visualization of the lumen of interest rather than relying only on a contrast-enhanced fluoroscopic image. Cholangioscopy and pancreatoscopy are the manifestation of this goal in the bile and pancreatic ducts, respectively. Since its introduction in 1970, per-oral cholangiopancreatoscopy (POCP) has evolved from a primarily diagnostic procedure performed in select centers, to current day widespread use for both diagnostic and therapeutic purposes. In 2015, an expert panel issued consensus statements providing a
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grading of established indications for POCP that ranged from the characterization of indeterminate strictures and directed sampling to therapeutic interventions such as management of difficult choledocholithiasis or guiding tumor ablation. (Table 1)
2. The Tools
Understanding the diverse available technologies for POCP will assist in our discussion regarding training and maintenance of competency for this procedure. Two basic systems are available and include the conventional endoscope-based ‘mother-daughter’ system (Olympus, Center Valley, PA and Pentax, New York ) and the fully disposable digital single-operator cholangiopancreatoscope (DSOCP) (SpyGlass DS, Boston Scientific, Marlborough, MA) in which a digital chip is housed in the tip of the catheter allowing for greater field of view, optical resolution, and tip deflection to improve maneuverability.(1, 2) An attractive potential of direct peroral cholangioscopy is that readily available endoscopes may be used for direct intraductal visualization and includes slim gastroscopes, standard gastroscopes and pediatric colonoscopes. It is notable, however, that Direct Peroral Cholangioscopy (DPOC) is not approved for intraductal visualization and these endoscopes tend to be difficult and bulky for facilitation of POCP.
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3. Established Indications
a. Cholangioscopy for characterization of biliary epithelium
Understanding established mucosal characteristics for neoplasia, albeit with low interobserver agreement even amongst experienced users, (3, 4) should assist in the development of training and competency programs for new and established adopters of POCP. The earliest descriptions were by Seo et al and Fukuda, et al in which malignant lesions had the characteristics that included: nodular, papillary, and infiltrative mucosal changes, along with neovascularization or ‘tumor vessels’.(2, 5) Further, less distinct features of friability and an irregular surface were described.
Benign strictures were felt
to have a smooth mucosa and borders without neovascularization, and papillogranular mucosa with no obvious mass. The addition using these criteria during POCP increased accuracy of diagnosing malignant strictures from 78.1% to 93.4% compared to ERC with tissue sampling, though inflammatory changes that include erythematous mucosa with erosive and ulcerative changes may lead to false positive cholangioscopic diagnoses(5-7). In a subsequent study using a video cholangioscope (POVCP) to assess similar criteria (Olympus TJF-240/260V; Olympus Medical Systems, Tokyo, Japan), sensitivity, specificity, and accuracy of 100%, 91.7%, and 97% were reported in the diagnosis of malignancy by visual findings (8). These features of irregular, dilated vessels, irregular surfaces, ulcerations, and polypoid or villous masses have been further described in studies using video cholangioscopy and yielding similar operating characteristics (6, 7, 9). Most recently, a study of 96 patients with a lower prevalence of malignancy in a U.S.
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patient population was performed to assess the operating characteristics of video cholangioscopy in the evaluation of indeterminate pancreaticobiliary strictures and found the sensitivity and specificity of the POVCP impression to be 85% and 84% respectively. The investigators also proposed a terminology for potentially neoplastic findings that included tortuous dilated vessels, ulceration, infiltrative stricture, polypoid mass, nodularity, friability, fish-egg lesion, and papillary type lesions. In biliary patients, tortuous vessels, infiltrative strictures, and the presence of a mass were found to be significantly associated with neoplasia. The presence of at least 1 feature had a sensitivity of 78% and specificity of 86% for the presence of neoplasia and 2 features had a sensitivity of 48% but a robust specificity of 96%. (10)
A significant limitation in advancing the field of POCP is a lack of uniformity on descriptive characteristics of mucosal lesions. Concern has been raised regarding the interobserver agreement for cholangioscopic findings with poor results from two studies using fiber optic images in which accuracy of diagnosing malignancy only reached 50% when viewed by biliary experts (3, 4). In a registry study from Japan using the fiberoptic SpyGlassTM system, designed much in the same way as the original multi-center registry study, 89 cholangioscopic exams were performed. Using established malignant criteria, the sensitivity was 94.7%, specificity 92.6%, and accuracy 94.0% (11). Prospective, multi-center data regarding the performance of DSOCP is awaited.
Additional complementary imaging modalities have been evaluated, such as narrow band imaging (NBI) and probe-based confocal imaging (pCLE). NBI works by restricting light
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to two wavelengths, 415 nm and 540 nm, providing enhanced visualization of superficial mucosal capillary and pit patterns, and thicker capillaries of the deeper tissues, respectively. In a feasibility study using a video cholangioscope (CHF-B260, Olympus Medical Systems, Tokyo, Japan) with an NBI system (CV-260SL processor, CVL-260Sl light source, Olympus) in determining lesion margins and to identify surface vessels using NBI, Itoi et al demonstrated improved visualization of the surface structure and vessels with NBI compared to high definition white light, as well as the detection of 4/21 lesions by NBI that were not seen by white light (12). The challenge to the use of NBI is its limited availability and interference by the dark red appearance of blood and bile.
Probe based confocal endomicroscopy, in which a laser light is passed through a confocal aperture providing histologic level images, can also be performed via cholangioscopy allowing for targeted evaluation and identification of imaging criteria that have been associated with malignancy. Given that this probe can be used in the absence of POCS, further discussion regarding results will be deferred other than to comment that early registry data demonstrated only a trend toward higher accuracy with cholangioscopyguided pCLE vs. catheter-based exams (13), but not statistically significant. However, additional prospective comparison studies using the refined criteria and the new Spy DS system have not been performed.
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b. POCP and Directly Visualized Targeted Biopsies
While visualization of biliary strictures and epithelium for characterization may have a role in the utility of POCP, one might argue that in the current oncologic setting, where diagnostic tissue acquisition is critical and has historically been challenging, the true value of this visualization is in the ability to obtain targeted biopsies. In order to optimize yield for malignancy detection, it is important that adopters of the technology familiarize themselves with established characteristics of malignancy to help distinguish from benign/reactive changes and guide sampling. Cytologic specimens from biliary brushings have resulted in notoriously poor yield with sensitivities of 23-56%(14-16) , which prompted a movement for combination sampling with fluoroscopy-guided forceps biopsy (FGB) and even intraductal fine needle aspiration(17). The introduction of miniature biopsy forceps added to the armamentarium of tissue acquisition methods. The first series of POCP-directed biopsies (POCP-DB) was reported over 10 years ago and yielded robust operating characteristics for the detection of neoplasia. Utilizing first generation single-operator cholangioscopy systems (SOC, Boston Scientific), a multicenter international registry by Chen et al actually demonstrated a decrease in sensitivity (49%) with directed biopsy compared to ERCP or visualization alone (78%), which the authors suggested may have been due to the inclusion of strictures caused by extrinsic compression (18). A systematic review found that overall sensitivity and specificity of SOCP-DB in detecting malignancy in the setting of previously negative findings, based on the inclusion of 4 studies, was 74.7% and 93.3% respectively (19). One group suggested that evaluating rapid on-site evaluation of touch preps of SOCP-DB specimens,
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reported a remarkable sensitivity of 100%, and accuracy of 93.5% in diagnosing malignancy with a mean of only 3.3 biopsies (range 1-8) (20) .
c.
Cholangioscopy-assisted stone therapy
Since the introduction of sphincterotomy, stone removal with balloon extraction and mechanical lithotripsy can successfully be used for duct clearance in 85-90% of cases. The remaining cohort of stones require advanced ERCP techniques that include electrohydraulic lithotripsy and laser lithotripsy. By providing an ability to directly visualize placement of the probes, as well as an ability to provide a saline-immersed environment, POCP has made both of the methods more widely-available and safe for the treatment of refractory stones and confirming duct clearance. The most commonly reported used POCP-guided laser lithotripsy is the Holmium laser which produces high energy waves that cause the stone to implode centrally. EHL employs a 1.9F insulated fiber, with a non-insulated tip that fits through the accessory channel of the cholangioscope and is attached to an electrical generator (Autolith, Nortech, Northgate Technologies Inc., Elgin, IL) that can deliver up to 30 pulses/sec. With the tip nearly touching the stone under direct visualization, application of the pulses results in water vaporization and transmission of the energy to the stone with resultant fragmentation. Alternatively, laser lithotripsy, most commonly using the holmium laser converts light energy to thermal energy which results in a layer of plasma formation at the surface with an internal bubble formation that expands causing an explosion of the stone from its central core. Due to the significantly intense energy levels of the probes, both methods have potential to cause significant damage to biliary epithelium if energy is
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inadvertently in contact with the epithelium, thus necessitating direct visualization for safe and effective use. When reviewing studies with greater than 20 patients that evaluated the efficacy and safety of POCP-guided biliary stone therapy, the overall stone clearance rate ranged from 66-92%, single session clearance in 70-80%, while the adverse event rate ranged from 4.8-18% (18, 21-25). To date, there is limited date comparing EHL and laser lithotripsy. While no specific guidelines exist, the standard practice prior to performing POCPguided therapy is to attempt treatment of stones with balloon extraction, endoscopic papillary balloon dilation, and/or mechanical lithotripsy. Additionally, an adequate sphincterotomy is essential both for allowing for the copious saline irrigation as well as to allow for retrieval and passage of fragmented stones from the duct during and following therapy. Lastly, the use of POCP for confirmation of ductal clearance may be considered. In one study, stones not seen on cholangiography were seen by POCS in 24% of cases (26). 4. Per Oral Pancreatoscopy (POP) a. The use of POP for evaluating pancreatic neoplasia The use of POP for characterization of intraductal papillary mucinous neoplasm and other pancreatic neoplasia is emerging in the U.S. and has been more established in East Asian populations with technical success rates of 73.2-100% and adverse events rates of 1.812%. Hara et al described five different types of IPMN and found that types 3-5, which included fish-egg-like protrusions with vascular images, villous protrusions, and vegative protrusions, were associated with malignant IPMN, with sensitivity, specificity, and accuracy of POP in differentiated the three types as 68%, 87%, and 75% (27). In a more
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recent study looking at a single center experience, including 78 patients, the sensitivity, specificity, and accuracy of POP visual impression alone in diagnosing pancreatic neoplasia was 87%, 86%, and 87% respectively. Directly visualized biopsies or assisted biopsies provided a similarly sensitivity, increased accuracy of 92% and 100% specificity. Together, the sensitivities were highest at 91%, and accuracy of 94% (28). Specific definitions of findings suggestive of normal, malignant and benign are found in table 3.
b. POP-guided pancreatic duct stone therapy Successful management of pancreatic intraductal stones via POP has been described both with EHL and laser lithotripsy though it remains a non-FDA approved indication. In a single-center study of 46 patients who underwent electrohydraulic or laser lithotripsy, complete or partial stone clearance was achieved in 91%, with complete clearance in 70% (29). Overall clinical success at 15 months was 74%, and pancreatoscopyrelated AE’s were mild (10%). In a multicenter retrospective study using laser lithotripsy for chronic calcific pancreatitis, 28 patients underwent POP exam with a median of 1 procedure (1-4). Onethird had undergone adjunctive extracorporeal shock wave lithotripsy and a quarter had failed or incomplete stone fragmentation with electrohydraulic lithotripsy. The technical success rate was 79% for complete stone clearance and the clinical success rate was 89% with clinical improvement at a median of 13 months’ follow-up based on a 50% reduction in pain, narcotic usage, or hospitalizations. symptoms. The mild adverse event rate was 29% (30).
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5. Selective cannulation Given the angulations at which ductal branches enter the common duct it would be apparent that direct visualization would facilitate selective cannulation and provide advantages to the two-dimensional aspect of fluoroscopy and to potentially reduce fluoroscopy time during selective wire manipulation. Specific settings in which this guidance may be helpful is in traversing obstructed intrahepatic ducts in the setting of hilar strictures, targeting intrahepatic strictures or stones, or cystic duct cannulation (3133) for transpapillary gallbladder stenting or therapy of cystic duct stones. The technique to use cholangioscopy for selective cannulation typically requires use of a long wire. Anecdotally, the author has experience with passing two .025” wires down the channel of the new digital SpyDSTM catheter in the case that two ducts need to be individually cannulated. The cholangioscope is then carefully removed from the duct with coordinated wire exchanges. Furthermore, direct visualization can be particularly helpful when there is near total occlusion of the duct, such as in anastomotic strictures in liver transplant patients or after post-surgical duct injury.
6. Direct Peroral Cholangioscopy (DPOC) As mentioned earlier, DPOC using ultra-slim gastroscopes has also been described. The limitation to this form of cholangioscopy is successfully managing to traverse the stomach and duodenum and cannulation of the bile duct. Several methods have been described to achieve this including free-hand cannulation using a withdrawal (J-type) maneuver where the gastroscope is extended distally to the papilla, the tip is deflected upward in the direction of the bile duct (or even bracing the orifice) and then the scope is
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reduced, sending the tip of the scope proximally up the duct (34). Other methods have been described for cannulation such as by first advancing a stiff guidewire during ERCP and exchanging the duodenoscope for a slim gastroscope over the guidewire. Similarly, the ultraslim scope can be advanced over a balloon-anchoring device that is either inserted via the duodenoscope or free hand via the ultraslim scope (35). Only one adverse event has been uniquely associated with DPOC, that of air embolism (36). The use of carbon dioxide and saline irrigation to assist with visualization are recommended. Once the duct is successfully cannulated with the slim scope and removal of the wire or catheter is performed, multiple maneuvers can carried out via the channel of scope including lithotripsy, biopsy, and even ablation with APC of intraductal neoplasia (37). However, stability and retention of the scope within the duct during interventions and traversing malignant strictures remains problematic.
7. Safety Reports of adverse events for POCP are difficult to assess in isolation given that this is a tandem exam to ERCP and is often performed in conjunction with therapeutic maneuvers that carry their individual associated adverse events, such as sphincterotomy, lithotripsy, balloon dilation, etc. Reported adverse events from single center studies with the use of SOC range from 4.3-13.3%, however (22-24, 31-33) this includes series in which procedures were performed for diagnostic and therapeutic purposes. These events include pancreatitis, cholangitis, perforation, fever abdominal pain, and bleeding. Only one study has evaluated the associated risk of performing POCP with ERCP to ERCP alone, in which 402 POCP exams were evaluated. Cholangiopancreatoscopy was found to be associated with an increased overall adverse event rate compared to ERCP alone and 12
specifically was associated with a significantly higher rate of cholangitis (1.0% vs. 0.2%) (38). It is noteworthy that the majority of the POCP exams evaluated in this study were with the older video cholangioscopy scopes not the SOC systems. In a large study of 282 SOC procedures only, in which diagnostic and therapeutic procedures were performed, adverse event rates were felt to be similar to large published series for ERCP with similar maneuvers (39). Additionally, in a large registry from Japan using the first generation SOC system, the overall procedure related adverse event rate was 5.4% (8/148)(11). It is unclear what advantages the new dedicated irrigation and aspiration channels of the second generation SpyTM system will offer with regard to adverse events. For the meantime, administration of antibiotics during POCP is routinely practiced.
8. Training, Achieving, and Maintaining Competency
Given the now widespread availability and utilization of cholangiopancreatoscopy systems, it is important to consider how best to provide and obtain sufficient training prior to implementing this technique into practice. In the previous grading systems for ERCP indications, cholangiopancreatoscopy was a level 4 procedure similar to hilar stricture evaluation and therapy and pancreatic endotherapy (40). It should be noted that at the time, cholangioscopy was performed primarily with the endoscope-based systems that were limited in distribution. Recently, a new grading system has been proposed, the H.O.U.S.E grading system that specifically places SOC and the associated maneuvers also in the highest complexity level (grade 3) (41). It stands to reason that if POCP is to be undertaken in one’s practice, that it be essential to mandate a baseline proficiency in
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these more complex ERCP indications. For the large, multi-center US and European SOC registry from over 10 years ago (18), a minimum of 10 procedures were required by each investigator prior to enrolling patients in the study. We now understand that image interpretation can be quite challenging (3, 4) and this number should likely be much higher to gain proficiency though guidelines on achieving competency are lacking. Further, it will be necessary to develop libraries of images and videos of established findings with their respective pathologic correlations to permit adjunctive tools for education of novice cholangiopancreatoscopy users. Though it is difficult to quantify a specific number necessary, given varying degrees of success and indications, prior to commencing a pancreatoscopy program, the authors would suggest performing a minimum of 20 cholangioscopy procedures and be well versed in therapeutic pancreatic stenting as a baseline surrogate.
The question of how established higher volume ERCP practitioners (likely those performing a minimum of 150 predominantly therapeutic ERCPs per year) may consider adapting this technology remains a difficult one to answer. The authors suggest that a combination of self-study, short preceptorship courses, and the utilization of hands-on models (1) to be necessary prior to commencing POCP. (Fig 1) Although formal advanced endoscopy training programs are now established, the volumes and case mix are quite varied. Thus, the ability to teach and acquire the necessary skills in its performance still remain institution dependent and although it could be expected that the skillset required to gain proficiency in other Grade 3 indications might be achieved by the
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conclusion of the training, achieving satisfactory cannulation rates alone may still require further mentorship beyond the 4th year fellowship year(42).
9. Suggested Guidelines
There is an absence of information on what metrics should be used to determine who should be performing POCP. Utilizing ERCP experience for complex indications could provide a surrogate metric to help determine a blueprint specific for POCP. Though within the U.S., guidelines on achieving and maintaining ERCP privileges remains essentially absent, the British Society of Gastroenterology in the U.K. taking input from various stakeholders, have embarked upon and begun to implement a volume and efficacy-based requirement to propose that ERCP be limited to intermediate and higher volume proceduralists (43) They provide an excellent example of precedence reviewing the colonoscopy improvement effort within the U.K. which resulted from an “…acceptance of the need for change, and a commitment to develop and adhere to key performance indicators…”. In the summary, an aim to achieve 100 ERCP’s per annum per provider and 200 cases per institution are proposed. Further, achieving a minimum of 85% biliary cannulation rate for native papillae and more than a 75% rate of stone clearance during the 1st ERCP session. Though the volume of respective case mix is not accounted for, it requires self-reporting of success rates, interventions, and adverse events for it to be potentially effective. There is a national financial incentive to report and a penalty to pay if metrics are not met and if the practice were continued by a specific provider or institution (personal communication).
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Beyond the proficiency in Level 3 and 4 ERCP for the prior to considering the use of POCP, having the necessary accessories, such as available intraductal lithotripsy systems and fibers, along with sufficiently trained staff in setup and assistance, are essential requirements for the successful performance of POCP.
10. Conclusion Cholangiopancreatoscopy has evolved significantly since its introduction in the 1970’s in technology as well as indications. Development of single operator disposable units has been instrumental in making this technique a routine component of pancreaticobiliary endoscopists practices. While pioneering characterization of intraductal pathology has been described by video cholangioscopy, the introduction of digital cholangioscopy and the improvement in visualization it provides, will allow for improved transfer of these criteria to everyday practice. Direct visualization for biopsy will remain an important indication for POCP as the need for improved methods of tissue acquisition persists. And while lithotripsy is the mainstay of POCP-guided therapy, the armamentarium of therapeutic procedures is sure to grow as new devices are developed that can fit through the accessory channels of currently available cholangioscopes. With the new widespread availability of POCP and expanding indications, efforts will need to be taken to ensure proper training in both technical performance as well as image interpretation and processing of data in the correct clinical context. This will likely best be accomplished by furthering efforts to develop training models and integrate these into competency algorithms that may include certification programs and preceptorships.
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Conflict of interest: Sethi-Boston Scientific, Olympus-Consultant Shah- Boston Scientific- Consultant
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26. Itoi T, Sofuni A, Itokawa F, Shinohara Y, Moriyasu F, Tsuchida A. Evaluation of residual bile duct stones by peroral cholangioscopy in comparison with ballooncholangiography. Dig Endosc. 2010;22 Suppl 1:S85-9. 27. Hara T, Yamaguchi T, Ishihara T, Tsuyuguchi T, Kondo F, Kato K, et al. Diagnosis and patient management of intraductal papillary-mucinous tumor of the pancreas by using peroral pancreatoscopy and intraductal ultrasonography. Gastroenterology. 2002;122(1):34-43. 28. El H, II, Brauer BC, Wani S, Fukami N, Attwell AR, Shah RJ. Role of per-oral pancreatoscopy in the evaluation of suspected pancreatic duct neoplasia: a 13-year U.S. single-center experience. Gastrointest Endosc. 2017;85(4):737-45. 29. Attwell AR, Brauer BC, Chen YK, Yen RD, Fukami N, Shah RJ. Endoscopic retrograde cholangiopancreatography with per oral pancreatoscopy for calcific chronic pancreatitis using endoscope and catheter-based pancreatoscopes: a 10-year single-center experience. Pancreas. 2014;43(2):268-74. 30. Attwell AR, Patel S, Kahaleh M, Raijman IL, Yen R, Shah RJ. ERCP with peroral pancreatoscopy-guided laser lithotripsy for calcific chronic pancreatitis: a multicenter US experience. Gastrointestinal Endoscopy. 2015;82(2):311-8. 31. Chen YK. Preclinical characterization of the Spyglass peroral cholangiopancreatoscopy system for direct access, visualization, and biopsy. Gastrointest Endosc. 2007;65(2):303-11. 32. Draganov PV, Chauhan S, Wagh MS, Gupte AR, Lin T, Hou W, et al. Diagnostic accuracy of conventional and cholangioscopy-guided sampling of indeterminate biliary lesions at the time of ERCP: a prospective, long-term follow-up study. Gastrointest Endosc. 2012;75(2):347-53. 33. Shah RJ, Langer DA, Antillon MR, Chen YK. Cholangioscopy and cholangioscopic forceps biopsy in patients with indeterminate pancreaticobiliary pathology. Clin Gastroenterol Hepatol. 2006;4(2):219-25. 34. Brauer BC, Chen YK, Shah RJ. Single-step direct cholangioscopy by freehand intubation using standard endoscopes for diagnosis and therapy of biliary diseases. Am J Gastroenterol. 2012;107(7):1030-5. 35. Waxman I, Dillon T, Chmura K, Wardrip C, Chennat J, Konda V. Feasibility of a novel system for intraductal balloon-anchored direct peroral cholangioscopy and endotherapy with an ultraslim endoscope (with videos). Gastrointest Endosc. 2010;72(5):1052-6. 36. Efthymiou M, Raftopoulos S, Antonio Chirinos J, May GR. Air embolism complicated by left hemiparesis after direct cholangioscopy with an intraductal balloon anchoring system. Gastrointest Endosc. 2012;75(1):221-3. 37. Brauer BC, Fukami N, Chen YK. Direct cholangioscopy with narrow-band imaging, chromoendoscopy, and argon plasma coagulation of intraductal papillary mucinous neoplasm of the bile duct (with videos). Gastrointest Endosc. 2008;67(3):5746. 38. Sethi A, Chen YK, Austin GL, Brown WR, Brauer BC, Fukami NN, et al. ERCP with cholangiopancreatoscopy may be associated with higher rates of complications than ERCP alone: a single-center experience. Gastrointest Endosc. 2011;73(2):251-6.
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39. Adler DG, Cox K, Milliken M, Taylor LJ, Loren D, Kowalski T, et al. A large multicenter study analysis of adverse events associated with single operator cholangiopancreatoscopy. Minerva Gastroenterol Dietol. 2015;61(4):179-84. 40. Cotton PB, Eisen G, Romagnuolo J, Vargo J, Baron T, Tarnasky P, et al. Grading the complexity of endoscopic procedures: results of an ASGE working party. Gastrointest Endosc. 2011;73(5):868-74. 41. Olsson G, Arnelo U, Swahn F, Tornqvist B, Lundell L, Enochsson L. The H.O.U.S.E. classification: a novel endoscopic retrograde cholangiopancreatography (ERCP) complexity grading scale. BMC Gastroenterol. 2017;17(1):38. 42. Wani S, Hall M, Wang AY, DiMaio CJ, Muthusamy VR, Keswani RN, et al. Variation in learning curves and competence for ERCP among advanced endoscopy trainees by using cumulative sum analysis. Gastrointestinal Endoscopy. 2016;83(4):711+. 43. Gastroenterology BSo. ERCP Working Party. ERCP – The Way Forward: A Standards Framework. 2014.
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Table 1:Indications for Cholangiopancreatoscopy Biliary stones that are not extractable using conventional and advanced techniques which include solely, or in combination of complete sphincterotomy, balloon or basket extraction, and dilation of downstream strictures and/or papilla Evaluation and targeted sampling of biliary strictures suspicious for malignancy Intraductal lithotripsy of main pancreatic duct stones (a non-FDA approved indication) The pre-operative assessment of main duct IPMN and to distinguish chronic pancreatitis from main duct IPMN in the appropriately dilated duct Emerging applications: a. Access to assist in traversing obstructed or tortuous biliary segments b. Guiding intraductal tumor ablation c. Assist in the extraction of inwardly migrated stents d. Surveillance of choledochal cysts Adapted from Consensus statement on Per Oral Cholangiopancreatoscopy (43)
Table 2: POVCP terminology(10) Proposed Neoplasia Findings Proposed Benign Findings Tortuous dilated vessels Ulceration “tumor vessels” Infiltrative stricture Nodularity Polypoid mass Concentric stenosis Vegetative mass Low-papillary mucosal lesion Fish-egg lesion Band-like scarring Finger-like villiform lesion Atrophy Erythema
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Figure 1. Benchtop Model for Potential Cholangioscopy Training
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S1096-2883(17)30061-X http://dx.doi.org/10.1016/j.tgie.2017.09.001 YTGIE50541
To appear in: Techniques in Gastrointestinal Endoscopy Cite this article as: Amrita Sethi and Raj Shah, Cholangioscopy and P a nc r e a t o s c o p y, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2017.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Cholangioscopy and Pancreatoscopy
Corresponding author: Amrita Sethi 168 Fort Washington Ave, Suite 852 New York New York, New York 10023 UNITED STATES 212-305-1909 Email: [email protected] Raj Shah Email: [email protected]
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Abstract Cholangiopancreatoscopy has evolved significantly since its introduction over 40 years ago. The systems have gone through multiple iterations that has allowed for widespread performance of per-oral cholangiopancreatoscopy (POCP) for diagnostic and therapeutic intent. Development of imaging criteria is evolving and its yield in the detection of neoplasia in conjunction with targeted tissue sampling is excellent. However, image interpretation remains a challenge. Guidelines for training in POCP, as well as demonstration of competency, are currently lacking but require deliberate debate as the technology continues to gather enthusiasm and momentum as an established complement to ERCP.
1-Introduction For endoscopists, the natural inclination is to have direct visualization of the lumen of interest rather than relying only on a contrast-enhanced fluoroscopic image. Cholangioscopy and pancreatoscopy are the manifestation of this goal in the bile and pancreatic ducts, respectively. Since its introduction in 1970, per-oral cholangiopancreatoscopy (POCP) has evolved from a primarily diagnostic procedure performed in select centers, to current day widespread use for both diagnostic and therapeutic purposes. In 2015, an expert panel issued consensus statements providing a
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grading of established indications for POCP that ranged from the characterization of indeterminate strictures and directed sampling to therapeutic interventions such as management of difficult choledocholithiasis or guiding tumor ablation. (Table 1)
2. The Tools
Understanding the diverse available technologies for POCP will assist in our discussion regarding training and maintenance of competency for this procedure. Two basic systems are available and include the conventional endoscope-based ‘mother-daughter’ system (Olympus, Center Valley, PA and Pentax, New York ) and the fully disposable digital single-operator cholangiopancreatoscope (DSOCP) (SpyGlass DS, Boston Scientific, Marlborough, MA) in which a digital chip is housed in the tip of the catheter allowing for greater field of view, optical resolution, and tip deflection to improve maneuverability.(1, 2) An attractive potential of direct peroral cholangioscopy is that readily available endoscopes may be used for direct intraductal visualization and includes slim gastroscopes, standard gastroscopes and pediatric colonoscopes. It is notable, however, that Direct Peroral Cholangioscopy (DPOC) is not approved for intraductal visualization and these endoscopes tend to be difficult and bulky for facilitation of POCP.
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3. Established Indications
a. Cholangioscopy for characterization of biliary epithelium
Understanding established mucosal characteristics for neoplasia, albeit with low interobserver agreement even amongst experienced users, (3, 4) should assist in the development of training and competency programs for new and established adopters of POCP. The earliest descriptions were by Seo et al and Fukuda, et al in which malignant lesions had the characteristics that included: nodular, papillary, and infiltrative mucosal changes, along with neovascularization or ‘tumor vessels’.(2, 5) Further, less distinct features of friability and an irregular surface were described.
Benign strictures were felt
to have a smooth mucosa and borders without neovascularization, and papillogranular mucosa with no obvious mass. The addition using these criteria during POCP increased accuracy of diagnosing malignant strictures from 78.1% to 93.4% compared to ERC with tissue sampling, though inflammatory changes that include erythematous mucosa with erosive and ulcerative changes may lead to false positive cholangioscopic diagnoses(5-7). In a subsequent study using a video cholangioscope (POVCP) to assess similar criteria (Olympus TJF-240/260V; Olympus Medical Systems, Tokyo, Japan), sensitivity, specificity, and accuracy of 100%, 91.7%, and 97% were reported in the diagnosis of malignancy by visual findings (8). These features of irregular, dilated vessels, irregular surfaces, ulcerations, and polypoid or villous masses have been further described in studies using video cholangioscopy and yielding similar operating characteristics (6, 7, 9). Most recently, a study of 96 patients with a lower prevalence of malignancy in a U.S.
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patient population was performed to assess the operating characteristics of video cholangioscopy in the evaluation of indeterminate pancreaticobiliary strictures and found the sensitivity and specificity of the POVCP impression to be 85% and 84% respectively. The investigators also proposed a terminology for potentially neoplastic findings that included tortuous dilated vessels, ulceration, infiltrative stricture, polypoid mass, nodularity, friability, fish-egg lesion, and papillary type lesions. In biliary patients, tortuous vessels, infiltrative strictures, and the presence of a mass were found to be significantly associated with neoplasia. The presence of at least 1 feature had a sensitivity of 78% and specificity of 86% for the presence of neoplasia and 2 features had a sensitivity of 48% but a robust specificity of 96%. (10)
A significant limitation in advancing the field of POCP is a lack of uniformity on descriptive characteristics of mucosal lesions. Concern has been raised regarding the interobserver agreement for cholangioscopic findings with poor results from two studies using fiber optic images in which accuracy of diagnosing malignancy only reached 50% when viewed by biliary experts (3, 4). In a registry study from Japan using the fiberoptic SpyGlassTM system, designed much in the same way as the original multi-center registry study, 89 cholangioscopic exams were performed. Using established malignant criteria, the sensitivity was 94.7%, specificity 92.6%, and accuracy 94.0% (11). Prospective, multi-center data regarding the performance of DSOCP is awaited.
Additional complementary imaging modalities have been evaluated, such as narrow band imaging (NBI) and probe-based confocal imaging (pCLE). NBI works by restricting light
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to two wavelengths, 415 nm and 540 nm, providing enhanced visualization of superficial mucosal capillary and pit patterns, and thicker capillaries of the deeper tissues, respectively. In a feasibility study using a video cholangioscope (CHF-B260, Olympus Medical Systems, Tokyo, Japan) with an NBI system (CV-260SL processor, CVL-260Sl light source, Olympus) in determining lesion margins and to identify surface vessels using NBI, Itoi et al demonstrated improved visualization of the surface structure and vessels with NBI compared to high definition white light, as well as the detection of 4/21 lesions by NBI that were not seen by white light (12). The challenge to the use of NBI is its limited availability and interference by the dark red appearance of blood and bile.
Probe based confocal endomicroscopy, in which a laser light is passed through a confocal aperture providing histologic level images, can also be performed via cholangioscopy allowing for targeted evaluation and identification of imaging criteria that have been associated with malignancy. Given that this probe can be used in the absence of POCS, further discussion regarding results will be deferred other than to comment that early registry data demonstrated only a trend toward higher accuracy with cholangioscopyguided pCLE vs. catheter-based exams (13), but not statistically significant. However, additional prospective comparison studies using the refined criteria and the new Spy DS system have not been performed.
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b. POCP and Directly Visualized Targeted Biopsies
While visualization of biliary strictures and epithelium for characterization may have a role in the utility of POCP, one might argue that in the current oncologic setting, where diagnostic tissue acquisition is critical and has historically been challenging, the true value of this visualization is in the ability to obtain targeted biopsies. In order to optimize yield for malignancy detection, it is important that adopters of the technology familiarize themselves with established characteristics of malignancy to help distinguish from benign/reactive changes and guide sampling. Cytologic specimens from biliary brushings have resulted in notoriously poor yield with sensitivities of 23-56%(14-16) , which prompted a movement for combination sampling with fluoroscopy-guided forceps biopsy (FGB) and even intraductal fine needle aspiration(17). The introduction of miniature biopsy forceps added to the armamentarium of tissue acquisition methods. The first series of POCP-directed biopsies (POCP-DB) was reported over 10 years ago and yielded robust operating characteristics for the detection of neoplasia. Utilizing first generation single-operator cholangioscopy systems (SOC, Boston Scientific), a multicenter international registry by Chen et al actually demonstrated a decrease in sensitivity (49%) with directed biopsy compared to ERCP or visualization alone (78%), which the authors suggested may have been due to the inclusion of strictures caused by extrinsic compression (18). A systematic review found that overall sensitivity and specificity of SOCP-DB in detecting malignancy in the setting of previously negative findings, based on the inclusion of 4 studies, was 74.7% and 93.3% respectively (19). One group suggested that evaluating rapid on-site evaluation of touch preps of SOCP-DB specimens,
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reported a remarkable sensitivity of 100%, and accuracy of 93.5% in diagnosing malignancy with a mean of only 3.3 biopsies (range 1-8) (20) .
c.
Cholangioscopy-assisted stone therapy
Since the introduction of sphincterotomy, stone removal with balloon extraction and mechanical lithotripsy can successfully be used for duct clearance in 85-90% of cases. The remaining cohort of stones require advanced ERCP techniques that include electrohydraulic lithotripsy and laser lithotripsy. By providing an ability to directly visualize placement of the probes, as well as an ability to provide a saline-immersed environment, POCP has made both of the methods more widely-available and safe for the treatment of refractory stones and confirming duct clearance. The most commonly reported used POCP-guided laser lithotripsy is the Holmium laser which produces high energy waves that cause the stone to implode centrally. EHL employs a 1.9F insulated fiber, with a non-insulated tip that fits through the accessory channel of the cholangioscope and is attached to an electrical generator (Autolith, Nortech, Northgate Technologies Inc., Elgin, IL) that can deliver up to 30 pulses/sec. With the tip nearly touching the stone under direct visualization, application of the pulses results in water vaporization and transmission of the energy to the stone with resultant fragmentation. Alternatively, laser lithotripsy, most commonly using the holmium laser converts light energy to thermal energy which results in a layer of plasma formation at the surface with an internal bubble formation that expands causing an explosion of the stone from its central core. Due to the significantly intense energy levels of the probes, both methods have potential to cause significant damage to biliary epithelium if energy is
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inadvertently in contact with the epithelium, thus necessitating direct visualization for safe and effective use. When reviewing studies with greater than 20 patients that evaluated the efficacy and safety of POCP-guided biliary stone therapy, the overall stone clearance rate ranged from 66-92%, single session clearance in 70-80%, while the adverse event rate ranged from 4.8-18% (18, 21-25). To date, there is limited date comparing EHL and laser lithotripsy. While no specific guidelines exist, the standard practice prior to performing POCPguided therapy is to attempt treatment of stones with balloon extraction, endoscopic papillary balloon dilation, and/or mechanical lithotripsy. Additionally, an adequate sphincterotomy is essential both for allowing for the copious saline irrigation as well as to allow for retrieval and passage of fragmented stones from the duct during and following therapy. Lastly, the use of POCP for confirmation of ductal clearance may be considered. In one study, stones not seen on cholangiography were seen by POCS in 24% of cases (26). 4. Per Oral Pancreatoscopy (POP) a. The use of POP for evaluating pancreatic neoplasia The use of POP for characterization of intraductal papillary mucinous neoplasm and other pancreatic neoplasia is emerging in the U.S. and has been more established in East Asian populations with technical success rates of 73.2-100% and adverse events rates of 1.812%. Hara et al described five different types of IPMN and found that types 3-5, which included fish-egg-like protrusions with vascular images, villous protrusions, and vegative protrusions, were associated with malignant IPMN, with sensitivity, specificity, and accuracy of POP in differentiated the three types as 68%, 87%, and 75% (27). In a more
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recent study looking at a single center experience, including 78 patients, the sensitivity, specificity, and accuracy of POP visual impression alone in diagnosing pancreatic neoplasia was 87%, 86%, and 87% respectively. Directly visualized biopsies or assisted biopsies provided a similarly sensitivity, increased accuracy of 92% and 100% specificity. Together, the sensitivities were highest at 91%, and accuracy of 94% (28). Specific definitions of findings suggestive of normal, malignant and benign are found in table 3.
b. POP-guided pancreatic duct stone therapy Successful management of pancreatic intraductal stones via POP has been described both with EHL and laser lithotripsy though it remains a non-FDA approved indication. In a single-center study of 46 patients who underwent electrohydraulic or laser lithotripsy, complete or partial stone clearance was achieved in 91%, with complete clearance in 70% (29). Overall clinical success at 15 months was 74%, and pancreatoscopyrelated AE’s were mild (10%). In a multicenter retrospective study using laser lithotripsy for chronic calcific pancreatitis, 28 patients underwent POP exam with a median of 1 procedure (1-4). Onethird had undergone adjunctive extracorporeal shock wave lithotripsy and a quarter had failed or incomplete stone fragmentation with electrohydraulic lithotripsy. The technical success rate was 79% for complete stone clearance and the clinical success rate was 89% with clinical improvement at a median of 13 months’ follow-up based on a 50% reduction in pain, narcotic usage, or hospitalizations. symptoms. The mild adverse event rate was 29% (30).
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5. Selective cannulation Given the angulations at which ductal branches enter the common duct it would be apparent that direct visualization would facilitate selective cannulation and provide advantages to the two-dimensional aspect of fluoroscopy and to potentially reduce fluoroscopy time during selective wire manipulation. Specific settings in which this guidance may be helpful is in traversing obstructed intrahepatic ducts in the setting of hilar strictures, targeting intrahepatic strictures or stones, or cystic duct cannulation (3133) for transpapillary gallbladder stenting or therapy of cystic duct stones. The technique to use cholangioscopy for selective cannulation typically requires use of a long wire. Anecdotally, the author has experience with passing two .025” wires down the channel of the new digital SpyDSTM catheter in the case that two ducts need to be individually cannulated. The cholangioscope is then carefully removed from the duct with coordinated wire exchanges. Furthermore, direct visualization can be particularly helpful when there is near total occlusion of the duct, such as in anastomotic strictures in liver transplant patients or after post-surgical duct injury.
6. Direct Peroral Cholangioscopy (DPOC) As mentioned earlier, DPOC using ultra-slim gastroscopes has also been described. The limitation to this form of cholangioscopy is successfully managing to traverse the stomach and duodenum and cannulation of the bile duct. Several methods have been described to achieve this including free-hand cannulation using a withdrawal (J-type) maneuver where the gastroscope is extended distally to the papilla, the tip is deflected upward in the direction of the bile duct (or even bracing the orifice) and then the scope is
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reduced, sending the tip of the scope proximally up the duct (34). Other methods have been described for cannulation such as by first advancing a stiff guidewire during ERCP and exchanging the duodenoscope for a slim gastroscope over the guidewire. Similarly, the ultraslim scope can be advanced over a balloon-anchoring device that is either inserted via the duodenoscope or free hand via the ultraslim scope (35). Only one adverse event has been uniquely associated with DPOC, that of air embolism (36). The use of carbon dioxide and saline irrigation to assist with visualization are recommended. Once the duct is successfully cannulated with the slim scope and removal of the wire or catheter is performed, multiple maneuvers can carried out via the channel of scope including lithotripsy, biopsy, and even ablation with APC of intraductal neoplasia (37). However, stability and retention of the scope within the duct during interventions and traversing malignant strictures remains problematic.
7. Safety Reports of adverse events for POCP are difficult to assess in isolation given that this is a tandem exam to ERCP and is often performed in conjunction with therapeutic maneuvers that carry their individual associated adverse events, such as sphincterotomy, lithotripsy, balloon dilation, etc. Reported adverse events from single center studies with the use of SOC range from 4.3-13.3%, however (22-24, 31-33) this includes series in which procedures were performed for diagnostic and therapeutic purposes. These events include pancreatitis, cholangitis, perforation, fever abdominal pain, and bleeding. Only one study has evaluated the associated risk of performing POCP with ERCP to ERCP alone, in which 402 POCP exams were evaluated. Cholangiopancreatoscopy was found to be associated with an increased overall adverse event rate compared to ERCP alone and 12
specifically was associated with a significantly higher rate of cholangitis (1.0% vs. 0.2%) (38). It is noteworthy that the majority of the POCP exams evaluated in this study were with the older video cholangioscopy scopes not the SOC systems. In a large study of 282 SOC procedures only, in which diagnostic and therapeutic procedures were performed, adverse event rates were felt to be similar to large published series for ERCP with similar maneuvers (39). Additionally, in a large registry from Japan using the first generation SOC system, the overall procedure related adverse event rate was 5.4% (8/148)(11). It is unclear what advantages the new dedicated irrigation and aspiration channels of the second generation SpyTM system will offer with regard to adverse events. For the meantime, administration of antibiotics during POCP is routinely practiced.
8. Training, Achieving, and Maintaining Competency
Given the now widespread availability and utilization of cholangiopancreatoscopy systems, it is important to consider how best to provide and obtain sufficient training prior to implementing this technique into practice. In the previous grading systems for ERCP indications, cholangiopancreatoscopy was a level 4 procedure similar to hilar stricture evaluation and therapy and pancreatic endotherapy (40). It should be noted that at the time, cholangioscopy was performed primarily with the endoscope-based systems that were limited in distribution. Recently, a new grading system has been proposed, the H.O.U.S.E grading system that specifically places SOC and the associated maneuvers also in the highest complexity level (grade 3) (41). It stands to reason that if POCP is to be undertaken in one’s practice, that it be essential to mandate a baseline proficiency in
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these more complex ERCP indications. For the large, multi-center US and European SOC registry from over 10 years ago (18), a minimum of 10 procedures were required by each investigator prior to enrolling patients in the study. We now understand that image interpretation can be quite challenging (3, 4) and this number should likely be much higher to gain proficiency though guidelines on achieving competency are lacking. Further, it will be necessary to develop libraries of images and videos of established findings with their respective pathologic correlations to permit adjunctive tools for education of novice cholangiopancreatoscopy users. Though it is difficult to quantify a specific number necessary, given varying degrees of success and indications, prior to commencing a pancreatoscopy program, the authors would suggest performing a minimum of 20 cholangioscopy procedures and be well versed in therapeutic pancreatic stenting as a baseline surrogate.
The question of how established higher volume ERCP practitioners (likely those performing a minimum of 150 predominantly therapeutic ERCPs per year) may consider adapting this technology remains a difficult one to answer. The authors suggest that a combination of self-study, short preceptorship courses, and the utilization of hands-on models (1) to be necessary prior to commencing POCP. (Fig 1) Although formal advanced endoscopy training programs are now established, the volumes and case mix are quite varied. Thus, the ability to teach and acquire the necessary skills in its performance still remain institution dependent and although it could be expected that the skillset required to gain proficiency in other Grade 3 indications might be achieved by the
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conclusion of the training, achieving satisfactory cannulation rates alone may still require further mentorship beyond the 4th year fellowship year(42).
9. Suggested Guidelines
There is an absence of information on what metrics should be used to determine who should be performing POCP. Utilizing ERCP experience for complex indications could provide a surrogate metric to help determine a blueprint specific for POCP. Though within the U.S., guidelines on achieving and maintaining ERCP privileges remains essentially absent, the British Society of Gastroenterology in the U.K. taking input from various stakeholders, have embarked upon and begun to implement a volume and efficacy-based requirement to propose that ERCP be limited to intermediate and higher volume proceduralists (43) They provide an excellent example of precedence reviewing the colonoscopy improvement effort within the U.K. which resulted from an “…acceptance of the need for change, and a commitment to develop and adhere to key performance indicators…”. In the summary, an aim to achieve 100 ERCP’s per annum per provider and 200 cases per institution are proposed. Further, achieving a minimum of 85% biliary cannulation rate for native papillae and more than a 75% rate of stone clearance during the 1st ERCP session. Though the volume of respective case mix is not accounted for, it requires self-reporting of success rates, interventions, and adverse events for it to be potentially effective. There is a national financial incentive to report and a penalty to pay if metrics are not met and if the practice were continued by a specific provider or institution (personal communication).
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Beyond the proficiency in Level 3 and 4 ERCP for the prior to considering the use of POCP, having the necessary accessories, such as available intraductal lithotripsy systems and fibers, along with sufficiently trained staff in setup and assistance, are essential requirements for the successful performance of POCP.
10. Conclusion Cholangiopancreatoscopy has evolved significantly since its introduction in the 1970’s in technology as well as indications. Development of single operator disposable units has been instrumental in making this technique a routine component of pancreaticobiliary endoscopists practices. While pioneering characterization of intraductal pathology has been described by video cholangioscopy, the introduction of digital cholangioscopy and the improvement in visualization it provides, will allow for improved transfer of these criteria to everyday practice. Direct visualization for biopsy will remain an important indication for POCP as the need for improved methods of tissue acquisition persists. And while lithotripsy is the mainstay of POCP-guided therapy, the armamentarium of therapeutic procedures is sure to grow as new devices are developed that can fit through the accessory channels of currently available cholangioscopes. With the new widespread availability of POCP and expanding indications, efforts will need to be taken to ensure proper training in both technical performance as well as image interpretation and processing of data in the correct clinical context. This will likely best be accomplished by furthering efforts to develop training models and integrate these into competency algorithms that may include certification programs and preceptorships.
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Conflict of interest: Sethi-Boston Scientific, Olympus-Consultant Shah- Boston Scientific- Consultant
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Table 1:Indications for Cholangiopancreatoscopy Biliary stones that are not extractable using conventional and advanced techniques which include solely, or in combination of complete sphincterotomy, balloon or basket extraction, and dilation of downstream strictures and/or papilla Evaluation and targeted sampling of biliary strictures suspicious for malignancy Intraductal lithotripsy of main pancreatic duct stones (a non-FDA approved indication) The pre-operative assessment of main duct IPMN and to distinguish chronic pancreatitis from main duct IPMN in the appropriately dilated duct Emerging applications: a. Access to assist in traversing obstructed or tortuous biliary segments b. Guiding intraductal tumor ablation c. Assist in the extraction of inwardly migrated stents d. Surveillance of choledochal cysts Adapted from Consensus statement on Per Oral Cholangiopancreatoscopy (43)
Table 2: POVCP terminology(10) Proposed Neoplasia Findings Proposed Benign Findings Tortuous dilated vessels Ulceration “tumor vessels” Infiltrative stricture Nodularity Polypoid mass Concentric stenosis Vegetative mass Low-papillary mucosal lesion Fish-egg lesion Band-like scarring Finger-like villiform lesion Atrophy Erythema
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Figure 1. Benchtop Model for Potential Cholangioscopy Training
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