Author: Edina Tari, Endre Botond Gagyi, Anett Rancz, Dániel Sándor Veres, Szilárd Váncsa, Péter Jen? Hegyi, Krisztina Hagymási, Péter Hegyi & Bálint Er?ss

Endoscopic RetrogradeCholangiopancreatography (ERCP) is the primary therapeutic procedure forpancreaticobiliary disorders, and studies highlighted the impact of papillaanatomy on its efficacy and safety. Our objective was to quantify the influenceof papilla morphology on ERCP outcomes. We systematically searched threemedical databases in September 2022, focusing on studies detailing thecannulation process or the rate of adverse events in the context of papillamorphology. The Haraldsson classification served as the primary system forpapilla morphology, and a pooled event rate with a 95% confidence interval wascalculated as the effect size measure. Out of 17 eligible studies, 14 wereincluded in the quantitative synthesis. In studies using the Haraldssonclassification, the rate of difficult cannulation was the lowest in type Ipapilla (26%), while the highest one was observed in the case of type IVpapilla (41%). For post?ERCP pancreatitis, theevent rate was the highest in type II papilla (11%) and the lowest in type Iand III papilla (6–6%).No significant difference was observed in the cannulation failure and post?ERCP bleeding event rates betweenthe papilla types. In conclusion, certain papilla morphologies are associatedwith a higher rate of difficult cannulation and post?ERCP pancreatitis.

Methods

A systematic review andmeta-analysis were conducted following the Preferred Reporting Items forSystematic Review and Meta-Analysis (PRISMA) Statement (see Supplementary Table12) and the recommendations of the Cochrane Handbook. The review protocol wasregistered in advance on PROSPERO with the registration number CRD42022360894.

Systematic search

Three databases: MEDLINE(via PubMed), Embase, and Cochrane Central Register of Controlled Trials(CENTRAL), were systematically searched from inception until the 29th ofSeptember 2022. We did not apply any filters or restrictions to our search. Themain parts of the search query included terms in connection with ERCP andpapilla morphology. For the detailed search strategy, see Table S1.Additionally, we systematically searched for relevant articles by reviewing theincluded articles’ bibliographic references and citation lists.

Eligibility criteria

Thecondition-context-population (CoCoPop) framework was used to identify eligiblestudies. The conditions were (Co): difficult cannulation, cannulation attempts,cannulation time, cannulation failure, post-ERCP pancreatitis, and otherpost-ERCP adverse events (bleeding, perforation, infection) in the context ofthe different papilla morphologies (Co). Studies with adult patients (> 18)undergoing ERCP with a native papilla (Pop) were selected. Randomizedcontrolled trials, case–control, cross-sectional, and cohort studies were eligible forinclusion. Both full-text articles and conference abstracts with sufficientdata were considered eligible. Regarding the definition of difficultcannulation, cannulation failure, and post-ERCP adverse events, the definitionsprovided in the included studies were used.

Morphology of thepapilla

Primarily, for theclassification of the morphology of the papilla, as the first validated intra-and interobserver classification, the Haraldsson system was used. Theyclassified the papilla into four types: regular (type 1), small (type 2),protruding or pendulous (type 3), and creased or ridged (type 4). Secondarily,a comparison between the Haraldsson and the other identified classificationsystems was attempted with the following method: two endoscopists (PJH, EB)assessed the description of the morphology and the imagery of the studies. Theychose the identical papilla types to Haraldsson’s. In case of any disagreement, athird reviewer was included in the decision process (ET). After the comparison,additional analyses were conducted.

Study selection and dataextraction

After the systematicsearch, the yielded articles were imported into a reference management program(EndNote X7.4, Clarivate Analytics, Philadelphia, PA, USA) to remove theduplicates automatically and manually. After removing duplicates, twoindependent authors (ET, EBG) screened the remaining publications first bytitle and abstract and then by full text. We used Rayyan for the selectionprocess. Cohen’s kappa coefficient (κ) was calculated onboth levels of selection to measure inter-reviewer reliability.

Discussion

Our systematic reviewand meta-analysis assessed the impact of papilla morphology on ERCP and itsoutcomes. We found that in studies using the Haraldsson classification,compared to the other papilla types, the event rate of difficult cannulationwas lower in type I papilla. Type II papilla was associated with a twofoldincrease in the event rate of PEP compared to the other papilla types. Therewas no difference in the cannulation failure and post-ERCP bleeding event ratesbetween the different papilla types.

Since its introduction,there have been debates regarding ERCP’s safety and success rate. Several factors seem to influencecannulation difficulties, such as age and age-related factors, includingduodenal distortion: procedure-related aspects, such as duodenal positioning orcertain etiologies, for example, malignant biliary obstruction. The morphologyof the papilla is also assumed to be related to multiple perspectives of theprocedure.

First, papillamorphology should be considered in the training of fellow endoscopists. In thestudies selected for inclusion, there are contradicting data regarding how theendoscopist’s expertise influences cannulation difficulty. Mohamed et al. foundno relationship between the rate of difficult cannulation and the endoscopist’s expertise. In contrast, in the study by Haraldsson et al., therate of difficult cannulation was the highest in type II papilla, where thenumber of trainees starting the cannulation process was the highest. Otherstudies also suggest that the operator’s experience maydecrease the rate of difficult cannulation and cannulation failure. Furtherdata in the literature suggest that the rate of PEP and other adverse eventsalso decreases with the endoscopist’s experience.

Secondly, papillamorphology also influences the rate of PEP, the procedure’s most commonadverse event. We found the highest rate of PEP in type II papilla, which isconsistent with the result of the individual studies. However, the definiteexplanation for this pattern is still uncertain. According to Chen et al.hypothesis, it could be due to the fact that endoscopic papilla balloondilatation (EPBD) was used more often in this papilla type in their cohort. Thesame trend could be observed in the study by Mohamed et al. Further data in theliterature suggest that EPBD with small-caliber balloons (diameter: 8–10 mm) increases the rate of PEP.

Lastly, all the includedstudies observed differences in rescue techniques’ use in different papillamorphologies. It could be one of the explanations for the non-significantdifference in cannulation failure between the different papilla types. Wehypothesize that the morphology of the papilla should be considered whenchoosing a rescue cannulation technique since it decreases the difference inthe tendency for cannulation failure or difficult cannulation between thepapilla types. Studies suggest that a pre-cut sphincterotomy or needle-knifefistulotomy (NKF) may be used in normal papillae. Trans-pancreaticsphincterotomy could be the recommended rescue technique in small papillae. Inprotruding/pendulous or creased/ridged papillae, also NKF could be thepreferred method.

Several classificationsystems were identified; the Haraldsson was the most widely used andwell-recognized one. Despite being the first validated classification systemdeveloped by expert endoscopists and, therefore, the basis of our analysis, ithas one major limitation: it ignores the presence of a periampullarydiverticulum. A modified version of the classification was proposed by Mohamedet al. in 2021, introducing an additional papilla type (type D) for papillaeinvolved with a periampullary diverticulum. In addition, a meta-analysis by Muiet al. found that the presence of PAD may increase the risk of cannulationfailure and may also be associated with a higher risk for post-ERCP adverseevents. These results suggest that this modified version of the classificationshould be used.

Strengths

Despite the topic’s importance, toour knowledge, this is the first meta-analysis focusing on papilla morphologyand its relation to the most relevant endpoints of the ERCP cannulation processand the rate of adverse events. A rigorous methodology was applied, with a comprehensivesearch key. No publication bias or outlier study was detected in any conductedanalyses, and most studies carried a low risk of bias. Moreover, the number ofincluded patients was above 20,000.

Limitations

Regardless of all thestrengths, this study also had some limitations: (1) In certain analyses,considerable statistical heterogeneity was observed. Its explanation could bethe clinical heterogeneity across studies, such as the difference in theapplied definitions in connection with the endoscopic procedure. Most studiesused the definition of the European Society of Gastrointestinal Endoscopy fordifficult cannulation; however, Thongsuwan et al. used its simplified version.(2) Some of the included cohort studies were retrospective analyses. (3) Thecertainty of the evidence was low or very low. (4) Abstracts were also eligiblefor inclusion; however, all were high-quality, containing all the necessarydata.

Implication for practice

Based on our results,during training of fellow endoscopists, papilla morphology should bedetermined, and trainees should start their learning with type I (“regular”) papillae. Using a unified classification system for papillamorphology is recommended to promote transparency in clinical practice.

Implication for research

Large sample cohorts areneeded to validate the Mohammed version of the classification and assess thepresence of a periampullary diverticulum. Besides the event rate, futureresearch should also focus on the severity of PEP in the different papillatypes. Furthermore, developing a recommendation system for advanced cannulationtechniques in the context of papilla morphologies should be considered.

Conclusion

In conclusion, othertypes are associated with a higher rate of difficult cannulation compared tothe regular papilla type. The small papilla is associated with a higher rate ofpost-ERCP pancreatitis.

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https://www.nature.com/articles/s41598-024-57758-9

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