The papilla of Vater : issues relevant to transpapillary cannulation and clinical management

Background: Many endoscopists have since the beginning of endoscopic retrograde cholangio-pancreatography (ERCP) commented on the variation in the macroscopic appearance of the papilla of Vater. How the macroscopic appearance of the papilla influences the cannulation efforts during ERCP has been discussed but not previously investigated in-depth. The endoscopic appearance can also be distorted by neoplastic lesions that can develop into cancer if not treated in time. Endoscopic papillectomy has evolved as a treatment option to cure these lesions if detected at an early stage. This thesis focuses on the influence of the endoscopic appearance on transpapillary cannulation, also how to clinically manage early neoplastic lesions situated in the papilla of Vater.

Objectives: I), To introduce a new inter- and intraobserver validated classification of the endoscopic appearance of the papilla of Vater. II), Apply the classification to investigate if the endoscopic appearance influences transpapillary cannulation during ERCP. III), Evaluate the minimally invasive method of endoscopic papillectomy in the treatment of early neoplastic lesions in the papilla of Vater, including evaluating the significance of KRAS analysis on the resected specimen. IV), To investigate what symptoms and preinterventional findings that could be of value for clinical decision-making when choosing the best method to resect ampullary neoplastic lesions when an invasive malignancy is not clear.

Methods: I) Constructing a web-based survey where 18 endoscopists categorized photos of 50 different papillae from the suggested classification. II). A Nordic multi-center study, measuring bile duct cannulation in 1401 patients after the papillae have been categorized into one of the distinct papilla types from the proposed classification. Determination of the frequency of difficult cannulation among the papilla types. III). A case series including 36 patients treated with endoscopic papillectomy, evaluating the clinical outcome and safety. Also, determining the status in the resected specimen of mutated KRAS to evaluate if that could predict the clinical prognosis. IV) A descriptive analysis of all patients treated with endoscopic papillectomy and/or surgical resection for verified or suspected ampullary neoplasia from 2006 to June 2018, where no invasive lesion was seen at cross-sectional imaging. Analyzing the symptoms, the histopathological results, and other investigational findings, comparing these with the final diagnosis after resection.

Results: The classification consisting of four distinct types of papillae showed a substantial inter- (κ=0.62) and intraobserver (κ=0.66) agreement among beginners as well as experienced endoscopists and was therefore possible to use in study II. The second study showed that bile duct cannulation was significantly more often difficult in small papilla, Type 2 (52%, 95% CI 45-59%) and protruding or pendulous papilla, Type 3 (48%, 95% CI 42-53%) compared to regular, Type 1 papilla (36%, 95% CI 33-40%). Failure to cannulate were more frequent if an inexperienced endoscopist started cannulation attempts. In study III 50% of the patients were cured from adenomatous neoplasia with endoscopic papillectomy. A small number of patients had mild to moderate complications. The results from KRAS analysis were hard to interpret. The preinterventional diagnosis changed in many patients after the endoscopic resection, raising questions that will be addressed in study IV. In study IV, if a histological diagnosis of malignancy could not be made before surgical resection, there was a high frequency of patients with benign or early neoplastic lesions treated with major pancreatic surgery. If endoscopic forceps biopsies show adenoma, endoscopic papillectomy has a curative potential in 59% of the patients.

Conclusions: 1. The macroscopic appearance of the papilla of Vater influences bile duct cannulation during ERCP, both among experts and beginner endoscopists: 2. Endoscopic papillectomy is a reasonably safe procedure with the potential to cure early neoplastic lesions in the papilla of Vater, and if not curative, offer a comprehensive tissue diagnosis that can guide clinical management. 3. Before deciding on surgical resection of a suspected neoplastic ampullary lesion, efforts must be made to get a histological confirmation of malignancy. When biopsies show adenoma, endoscopic papillectomy should be considered to cure the patient or at any rate get a confirmation of malignant disease.

List of scientific papers

I. Haraldsson, E., Lundell, L., Swahn, F., Enochsson, L., Löhr, J., Arnelo, U. (2016). Endoscopic classification of the papilla of Vater. Results of an inter- and intraobserver agreement study. United European Gastroenterology Journal. 5(4), 504-510.
https://doi.org/10.1177/2050640616674837

II. Haraldsson, E., Kylänpää, L., Grönroos, J., Saarela, A., Toth, E., Qvigstad, G., Hult, M., Lindström, O., Laine, S., Karjula, H., Hauge, T., Sadik, R., Arnelo, U. (2019). The macroscopic appearance of the major duodenal papilla influences bile duct cannulation: a prospective multicenter study by the Scandinavian Association for Digestive Endoscopy study group for ERCP. Gastrointestinal Endoscopy. 90(6), 957-963.
https://doi.org/10.1016/j.gie.2019.07.014

III. Haraldsson, E., Swahn, F., Verbeke, C., Mattsson, J., Enochsson, L., Ung, K., Lundell, L., Heuchel, R., Löhr, J., Arnelo, U. (2015). Endoscopic papillectomy and KRAS expression in the treatment of adenoma in the major duodenal papilla. Scandinavian Journal of Gastroenterology. 50(11), 1419-1427.
https://doi.org/10.3109/00365521.2015.1046912

IV. Haraldsson, E., Halimi, A., Al-Saffar, H.A., Zarantonello, L., Rangelova, E., Löhr, J.M., Arnelo, U. Endoscopic and/or surgical resection for adenomatous neoplasia in the papilla of Vater - The Karolinska Experience 2006-2018. [Manuscript]