From September 2006 to April 2012, 39 consecutive patients with ampullary adenoma underwent EP at a high-volume tertiary referral center. During the same period, 3332 endoscopic retrograde cholangiopancreatography (ERCP) procedures, including 2437 diagnostic and 895 therapeutic procedures, were performed. Thus, 1.2% of all ERCPs and 4.4% of therapeutic ERCPs were carried out for EP. Included patients were grouped according to the occurrence of procedure-related complications: no complication group (without complication, n=28) and complication group (with complication, n=11).

We retrospectively analyzed the clinical, laboratory, endoscopic, and histologic data which were prospectively recorded. Treatment outcomes were categorized as endoscopic and clinical. Endoscopic outcomes included en block resection, complete resection, and endoscopic success. En bloc resection was defined as resection in a one-piece fashion with no residual tumor viewed endoscopically. Complete resection was defined as resection in the absence of any remnant lesion or recurrence in control biopsies at the end of the study regardless of the number of treatment sessions.6,10 Endoscopic success was defined as total removal via excision, irrespective of the number of sessions required for removal, and absence of recurrence or recurrence during the follow-up period, treated sufficiently by EP.11 Clinical outcomes included duration of antiprotease injection during the hospital stay, transfusion requirement, length of hospital stay, mortality, and recurrence.

The pre-procedural diagnosis of ampullary adenoma was obtained for each patient by forceps biopsy. Endoscopic ultrasound (EUS), transpapillary intraductal ultrasound (IDUS), ERCP, and computed tomography or magnetic resonance image were applied for the assessment of the extent of the tumor.

An indication for EP was based on EUS, IDUS, and ERCP findings that showed that the tumor had not infiltrated the bile or pancreatic ducts and that the adenoma or cancer invasion was confined to the mucosa.6,10 Patients with invasive carcinoma, metastatic disease, coagulation abnormalities, or severe concomitant disorders were not indicated for ampullectomy. Patients with ampullary adenoma in familiar adenomatous polyposis were excluded. Written informed consent was obtained from all patients. This study was approved by the Institutional Review Board of Yonsei University College of Medicine, Korea.

EP was performed by five expert endoscopists with patients under sedation. The entire procedure was carried out under fluoroscopic guidance using a side-view duodenoscope (TJF 260; Olympus, Tokyo, Japan). EP was performed using one of the following methods: 1) snare papillectomy or 2) endoscopic mucosal resection (EMR). For en block resection, we performed EP by grasping the adenoma at the base with a standard polypectomy snare and applying an Endocut current effect 2 using an ERBE generator. The EMR was performed for only periampullary portion, because the submucosal injection of papilla can also make the lesion difficult to capture using a snare.12 Small, remnant lesions unamenable to snare resection were either removed by endoscopic forceps or fulgurated by argon plasma coagulation (APC; ERBE Elektromedizin, Germany). The placement of a pancreatic stent was routinely performed. The application of biductal sphincterotomy or biliary stent was individualized in each case.

As EP and biliary or pancreatic sphincterotomy are higher-risk procedures for bleeding, we weighted the benefit of discontinuation of anti-platelets (aspirin and non-steroidal anti-inflammatory drugs) against the risk of thromboembolic events. We discontinued aspirin and/or non-steroidal anti-inflammatory drugs for 5 to 7 days before the procedure, depending on the underlying indication for antiplatelet therapy.13 We used antiprotease including nafamostat and gabexate mesylate: 50 mg of nafamostat was infused intravenously twice a day and 600 mg of gabexate mesylate intravenously once a day.

We classified the macroscopic type of lesion as an exposed type vs. an unexposed type, based on a previous macroscopic classification of carcinoma of the ampulla of Vater.7 We defined the exposed type of lesion as polypoid tumors protruding through the papilla into the duodenum (periampullary type). The unexposed type was defined as polypoid tumors of the common channel without a duodenal luminal component (intraampullary type), or a mixed form of periampullary and intraampullary type.

Resected specimens were diagnosed according to the revised Vienna classification.14 Histologic grading was classified as low-grade dysplasia (LGD), high-grade dysplasia (HGD), differentiated adenocarcinoma, and undifferentiated adenocarcinoma. The positivity of vertical and lateral cuts of the resected specimen was examined to confirm complete endoscopic resection.

Complications were classified into early (pancreatitis, bleeding, perforation, and others) or late (post-papillectomy stenosis) onset. EP-related pancreatitis was defined according to consensus criteria.15 It was diagnosed if there was an elevation in pancreatic enzymes of at least three times the upper limit of the normal range 24 hours after the procedure, new onset of pain in the upper abdomen, and hospitalization for at least 2 days. The grade of pancreatitis severity was also determined according to consensus guidelines; mild EP-related pancreatitis resulting in a hospitalization of less than or equal to 3 days; moderate EP-related pancreatitis resulting in a hospitalization of 4 to 10 days; and severe EP-related pancreatitis resulting in a hospitalization of 11 or more days, leading to the development of pancreatic necrosis or pseudocyst, or requiring percutaneous or surgical intervention. Bleeding was diagnosed if there was clinical or endoscopical evidence of bleeding after completion of the procedure. The clinical or endoscopic evidence comprised the following: 1) fresh hematemesis or fresh blood passing from the nasogastric tube; 2) passage of fresh melena or hematochezia with evidence of bleeding (a systolic blood pressure <100 mm Hg, a heart rate >100 bpm, or a drop in hemoglobin level of >2 g/dL within 24 h); and 3) bleeding demonstrated by endoscopy.

Follow-up endoscopy with forceps biopsy was scheduled after 3 to 6 months and at yearly intervals thereafter. A second endoscopy was not performed routinely. If the resected lesion recurred and additional endoscopic treatment was possible, endoscopic treatment was performed every 2 to 3 months until there was no residual adenoma, with surveillance every 6 to 12 months for the next 2 years according to the recommendations.16 When the patient had a small lesion with tubular adenoma, the interval of endoscopic surveillance was increased to 2 or 3 years gradually. Surgical resection was done if additional endoscopic treatment was not feasible.

Statistical analysis included the chi-square test, Fisher's exact test, and Mann-Whitney U test. Results were presented as proportions, or median with range (minimum-maximum) as indicated. Kaplan-Meier's test and log-rank test were performed for the evaluation of recurrence rate and comparison of recurrence rate between two groups, respectively. A p value <0.05 was considered statistically significant. Statistical analysis was performed using the SAS program (version 9.2, SAS Institute, Cary, NC, USA).

This study included 39 patients (23 men and 16 women; median age 62.0 years, range 34.0-88.0 years). There were no significant differences in baseline characteristics, including age, gender, and the use of antiplatelets, anticoagulation, and comorbidities, between the no complication group (n=28) and the complication group (n=11) (Table 1). There was no significant difference in the distribution of five endoscopists between the two groups (p=0.074).

Clinically, the presence of symptoms, including pancreatitis prior to EP was similar in the two groups. In laboratory characteristics, amylase (median 111 IU/L vs. 361 IU/L, p=0.006) and lipase levels (median 67 IU/L vs. 457 IU/L, p=0.007), 24 hours after EP, were significantly higher in the complication group than in the no complication group. However, amylase and lipase levels within 24 hours after EP and other laboratory serologic values, including hemoglobin levels, white blood cell count, platelet count, aspartate transaminase, and alanine transaminase levels, total bilirubin, and albumin levels were not significantly different between the two groups.

The complications of EP are summarized in Table 2. Fifteen complications from 11 patients (28.2%) occurred, and all were early complications. The most common complication was EP-related pancreatitis (n=7, 17.9%), followed by bleeding (n=4, 10.3%) and perforation (n=2, 5.1%). Seven EP-related cases of pancreatitis were composed of grade 2 (n=5) and grade 3 (n=2) pancreatitis. They were successfully managed with medical treatment, including fasting, intravenous hydration, and antiprotease injection. No necrotizing pancreatitis or pancreatic pseudocysts developed during EP-related pancreatitis. Four patients experienced procedure-related bleeding, which was managed with endoscopic clips, electric coagulation, or APC. Two patients with perforations were managed with endoscopic clips and medical treatments. Two patients developed pneumonia after the procedure, which was managed without further complications. No cholangitis or biliary stenosis occurred. None of the patients underwent any surgeries for complication management.

We analyzed the endoscopic and histologic characteristics of the two groups (Table 3). Endoscopic characteristics including the size and type of lesion, placement of pancreatic or biliary duct stent after EP, performance of biductal sphincterotomy, and resection method (snare papillectomy vs. EMR) did not reveal any significant differences. The sizes and lengths of stents ranged from 5 to 8 Fr and from 5 to 7 cm, respectively. The histologic diagnosis of resected specimens was not significantly different between the two groups (p=0.541), however, was associated with complete resection rate. The complete resection rate in LGD (n=24), HGD (n=7), adenocarcinoma (n=3), and benign tissue (n=5) was 83.3%, 42.9%, 33.3%, and 100%, respectively (p=0.032). Thus, it appears that as the tumor progressed from adenoma to cancer, the complete resection rate decreased.

The overall en block resection rate, complete resection rate, and endoscopic success rate were 89.7%, 74.4%, and 92.3%, respectively. The overall median value of the duration of antiprotease injection during the hospital stay and length of hospital stay were 3.0 days (range 1.0-18.0 days) and 8.0 days (range 4.0-24.0 days), respectively. Thirty-two of the enrolled patients (82.1%) received anti-protease agents. There was no mortality in the present study. Treatment outcomes of the two groups are listed in Table 4. The en block resection rate, complete resection rate, and endoscopic success rate did not differ significantly between the two groups. Clinically, the duration of antiprotease injection during the hospital stay was significantly longer (median 2.0 days vs. 5.0 days, p=0.017) and the transfusion requirements were significantly higher (0% vs. 27.3%, p=0.018) in the complication group than the no complication group. The hospital stay tended to be longer (median 6.5 days vs. 9.0 days, p=0.083) in the complication group. During a median follow-up period of 15 months (range 1-25 months), three lesions (10.3%) recurred among patients with complete resection (n=29) and five lesions (12.8%) recurred among enrolled patients. In three HGD lesions and two LGD lesions, recurrence occurred. However, the histology at the time of recurrence sometimes differed from the prior histology of the resected specimen. In one patient with previously resected HGD, LGD occurred. In another patient with resected LGD, adenocarcinoma occurred. In the latter case, a pathological examination revealed that the resection margin was clear at the time of ampullectomy, but pancreaticoduodenectomy was performed 22 months later, because of the occurrence of adenocarcinoma. Additionally, the recurrence was not associated with the initial size of the lesion, as the lesions without recurrence and with recurrence did not show a significant difference in lesion size (p=0.281).