Contemporary Results with Ampullectomy for 29 Benign Neoplasms of the Ampulla

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1 Contemporary Results with Ampullectomy for 29 Benign Neoplasms of the Ampulla Stephen R Grobmyer, MD, Chad N Stasik, MD, Peter Draganov, MD, Alan W Hemming, MD, FACS, Lisa R Dixon, MD, Stephen B Vogel, MD, FACS, Steven N Hochwald, MD, FACS BACKGROUND: STUDY DESIGN: RESULTS: CONCLUSIONS: Ampullectomy may be an appropriate oncologic procedure in selected patients. Sparse data exist on procedure-related complications and the relationship between histologic analysis and outcomes. We retrospectively reviewed our experience with ampullectomy in 29 patients with a preoperative benign histologic diagnosis over 15 years (1991 to 2006). Presenting signs, symptoms, and preoperative diagnostic studies were reviewed. Postoperative complications and followup for recurrence were recorded. The abilities of preoperative histologic biopsy, intraoperative frozen section, and final histologic analysis to guide management and predict outcomes were determined. Median age was 63 years. Jaundice was present in 30% of patients. Median length of hospital stay was 9 days. Forty-five percent of patients had a complication, and there was one postoperative mortality (3%). Ampullary adenomatous neoplasms were present in 89% of patients. Preoperative biopsy had complete concordance with final pathology in 76% of patients. Preoperative biopsy and intraoperative frozen section failed to identify carcinoma in four patients. Pancreaticoduodenectomy was performed within 7 days in the postoperative period in three of these patients. After ampullectomy (median followup 16 months), recurrences were identified in two patients (8%) with benign tumors. No patients with high-grade dysplasia (n 4) have had recurrence. Preoperative biopsy and intraoperative frozen section analysis have limitations in the management of patients undergoing ampullectomy. High-grade dysplasia on preoperative biopsy is not an absolute contraindication to ampullectomy. Morbidity of ampullectomy is significant, but longterm outcomes of this procedure, in patients without invasive malignancy, are acceptable. (J Am Coll Surg 2008;206: by the American College of Surgeons) Ampullary tumors account for 10% of periampullary neoplasms and can occur sporadically or in the setting of familial polyposis syndromes. Benign neoplasms of the ampulla of Vater are rare overall and have been identified in 0.04% to 0.12% in autopsy series. 1 But they are being recognized with increasing frequency because of the extensive use of flexible endoscopy. Although classified as benign, ampullary adenomas are premalignant neoplasms arising from the mucosa. It is Competing Interests Declared: None. Received May 24, 2007; Revised July 30, 2007; Accepted September 4, From the Divisions of Surgical Oncology and Endocrine Surgery (Grobmyer, Stasik, Vogel, Hochwald), Gastroenterology (Draganov), and Transplantation and Hepatobiliary Surgery (Hemming), and the Department of Pathology, Immunology and Laboratory Medicine (Dixon), University of Florida, Gainesville, FL. Correspondence address: Steven N Hochwald, MD, University of Florida College of Medicine, 1600 SW Archer Rd, PO Box , Gainesville, FL thought that the adenoma-to-carcinoma sequence does occur for these lesions. Grossly and histologically, these lesions are similar to the adenomas arising in the mucosa of the large intestine. 2 In the colon, certain factors, including adenoma type, location, size, and multicentricity are thought to increase the chance of finding malignant change within the adenomatous lesions. Although less information is available for small bowel adenomas, similar factors seem to be able to predict behavior of these tumors of the small bowel. 3 In support of this finding, in one study of 51 patients with ampullary tumors, the average size of adenomas was 2.7 cm, and it was 3.7 cm for adenomas with coexistent carcinoma and 4.7 cm for pure adenocarcinomas. 2 Surgeons must rely on preoperative biopsy and intraoperative frozen section analysis in making decisions about the proper surgical procedure for ampullary tumors. Unfortunately, contemporary data on the accuracy of these analyses are sparse in the literature. Although local excision of ampullary neoplasms was first 2008 by the American College of Surgeons ISSN /08/$34.00 Published by Elsevier Inc. 466 doi: /j.jamcollsurg

2 Vol. 206, No. 3, March 2008 Grobmyer et al Ampullectomy for Benign Ampulla Neoplasms 467 described by Halsted in 1899, 4 it failed to achieve widespread acceptance because of the high rate of tumor recurrence. In addition, because many centers have developed expertise in pancreaticoduodenectomy for peripancreatic tumors, there is an increased tendency to use this operation for all ampullary tumors. 5,6 In experienced centers, pancreaticoduodenectomy is associated with low mortality rates, but high rates of perioperative morbidity. 7 Ampullectomy is potentially an attractive alternative in appropriate patients because it may be associated with lower morbidity. Because of the small numbers of patients reported in the literature undergoing ampullectomy for ampullary tumors, clinical features and outcomes of these patients have not been well described. Our objective was to review our experience with a large number of patients who underwent ampullectomy for lesions without invasive malignancy on preoperative assessment during a recent time period. METHODS After Institutional Review Board approval was obtained, our ampullary tumor database was queried to identify patients undergoing ampullectomy from January 1991 to December All patients with a diagnosis of familial adenomatosis polyposis were excluded from additional analysis. Patients with the preoperative diagnosis of invasive carcinoma of the ampulla were excluded from this study. Surgical decision making was at the discretion of the treating physician and was independent of any protocol. The University of Florida Department of Pathology reviewed all preoperative pathology specimens. s were classified as predominantly tubular, villous, or mixed tubulovillous. The grade of dysplasia and presence of malignancy were evaluated in the preoperative biopsy, intraoperative frozen section analyses, and final pathologic analyses. Preoperative evaluation included laboratory evaluation including liver function tests, upper endoscopy with ERCP, and CT. Endoscopic ultrasonography was performed by one of the authors in a subset of patients, and an assessment of T-stage was made using the standard TNM classification for ampullary tumors. Ampullectomy was performed as previously described, through an open surgical approach in 26 of the 29 patients. 8 The other three patients underwent endoscopic resection of the ampulla. Complications were retrospectively recorded according to predetermined criteria. Specifically, pneumonia was defined by the combination of fever, x-ray findings, and need for antibiotic therapy. Wound infections were defined by the findings of wounds that required opening or were culture positive. Pancreatic fistula was defined by high amylase Table 1. Demographics of 29 Patients Undergoing Ampullectomy Symptoms n % Median age, y (range) 63 (34 81) Abdominal pain Jaundice 8 30 Weight loss 5 19 Vomiting 3 11 Incidental 3 11 Fevers/chills 2 7 Abnormal liver function tests 2 7 Pancreatitis 1 4 Diarrhea 1 4 Preoperative biliary drainage Biliary stent 7 26 Sphincterotomy 4 15 T tube 1 4 Familial cancer syndromes Neurofibromatosis Familial adenomatous polyposis 0 ( 5 times normal) content in fluid from a drain after postoperative day 7 or ( 50 ml) drain fluid output after day 10. Followup data were obtained from hospital and office records and direct patient contact. RESULTS A retrospective review of patient records revealed 29 patients who underwent ampullectomy during this period. During this same time, twice as many patients were explored for attempted ampullectomy, which was aborted because of lesion size or location, concern for malignancy, or documented malignancy at the time of operation. Patient demographics are shown in Table 1. The most common presenting symptoms were abdominal pain (47%) and jaundice (30%). Seven patients had a biliary stent placed for treatment of abnormal liver function tests or relief of jaundice before ampullectomy. Neurofibromatosis was present in one patient, but no patient had familial adenomatous polyposis syndrome. Preoperative diagnostic studies included CT, esophagogastroduodenoscopy (EGD), ERCP, or endoscopic ultrasonography (EUS). EGD and ERCP were the most useful tests in the diagnosis and preoperative evaluation of the patients in this study. A mass was seen on endoscopic ultrasonography or ERCP in all patients. ERCP revealed intrahepatic or extrahepatic ductal dilation in 12 of 26 patients (46%). Pancreatic ductal dilation was seen in 2 of 26 patients (8%) at ERCP. In 23 patients undergoing CT, intrahepatic or extrahepatic ductal dilation was seen in 7 patients (30%). Of note, pancreatic ductal dilation was

3 468 Grobmyer et al Ampullectomy for Benign Ampulla Neoplasms J Am Coll Surg Table 2. Accuracy of Endoscopic Ultrasonography for Ampullary Neoplasms EUS EUS results Final path accurate? No invasion Yes No invasion Yes No invasion Carcinoid Yes No penetration beyond Carcinoid Yes muscularis Mucosal involvement Tubulovillous with Yes HGD Confined to mucosa Polypoid adenoma Yes T2N0 No T1 with HGD No T2 or T3 No T1 No Accuracy of ultrasonography 6/10 60% EUS, endoscopic ultrasonography; HGD, high-grade dysplasia. Table 3. Limitations of Preoperative Biopsy for High-Grade Dysplasia and Preoperative biopsy Final pathology Correct, HGD, HGD, HGD, HGD Incorrect, HGD, HGD with focal HGD, focal HGD HGD, high-grade dysplasia. seen in only 1of 23 patients (4%). No patient with a benign ampullary polyp had evidence of dilation of both the bile duct and pancreatic duct by CT scan or ERCP evaluation. Jaundice was present in eight patients in this study. Of the four patients with a final diagnosis of ampullary adenocarcinoma, all patients presented with jaundice. But the other four patients with jaundice had benign disease, some with high-grade dysplasia in the specimen. Jaundice is indicative of a higher risk for the presence of carcinoma, but not all patients presenting with jaundice have carcinoma. Data from EUS were available in 10 patients. EUS predicted the appropriate extent of tumor invasion into the ampullary sphincter in 6 of 10 patients (Table 2). The tendency on EUS was to overestimate the degree of invasion of the tumor through the mucosa of the ampulla. All patients had a benign diagnosis based on preoperative biopsy. Twenty-six of 29 patients had an adenomatous neoplasm; 3 patients had a carcinoid tumor on preoperative biopsy. Four patients who had a preoperative biopsy of benign ampullary neoplasm displayed invasive carcinoma on final histologic analysis. Median tumor size was 2 cm for all patients, with a range of 0.5 cm to 4.5 cm. Preoperative biopsy had exact concordance with final excisional histologic analysis in 22 of 29 specimens (76%). In four tumors that had high-grade dysplasia on final excisional pathology, preoperative biopsy correctly identified the severity of dysplasia in two and missed the presence of severe dysplasia in the other two. One patient who had high-grade dysplasia on preoperative biopsy was not found to have any additional high-grade dysplasia on final pathologic analysis. This was explained by the presence of inflammatory changes in the biopsy specimen, which were misinterpreted as high-grade dysplasia. Preoperative biopsy did not detect the presence of carcinoma in all four patients with invasive carcinoma on final histologic analysis (Table 3). Preoperative biopsy revealed an adenoma with varying degrees of villous features in all of these patients. Highgrade dysplasia was seen on preoperative biopsy in only one tumor that had invasive carcinoma on final histologic analysis. Intraoperative frozen section analysis was performed in 17 patients. Overall, frozen sections had concordance with final pathologic analysis in 15 of 17 patients (88%). Frozen sections correctly identified two patients with adenomas and high-grade dysplasia, one of which was definitely identified, and the other was considered probable (but defer to permanent). Of the four patients with carcinoma on final pathology, two had an intraoperative frozen section. Unfortunately, the carcinoma was not detected on frozen section analysis in either patient (Table 4). Although ampullectomy was the initial procedure in all patients in this study, three patients underwent pancreaticoduodenectomy within 2 weeks of the ampullectomy. This was done for three of the four patients who exhibited carcinoma on final pathologic analysis. Although pancreaticoduodenectomy was recommended to all patients with carcinoma on final pathologic analysis, one patient refused pancreaticoduodenectomy in the immediate postoperative period. The median length of stay after surgical ampullectomy was 9 days (range 6 to 58 days). Thirteen of 29 patients (45%) had at least 1 complication. The most frequent complications are shown in Table 5. Two patients received a blood transfusion in the postoperative period. One patient had cirrhosis and liver dysfunction and required transfusion. The other patient who received a transfusion had a prolonged hospital stay (58 days), with complications including duodenal leak and biliary fistula. There was one

4 Vol. 206, No. 3, March 2008 Grobmyer et al Ampullectomy for Benign Ampulla Neoplasms 469 Table 4. Accuracy of Intraoperative Frozen Section Frozen section Final pathology with suspicion for HGD with focal HGD with focal HGD Tubular adenoma with HGD with HGD Polypoid adenoma Polypoid adenoma Tubular adenoma Tubular adenoma Tubular adenoma No adenoma Papillary stenosis Papillary stenosis HGD, high-grade dysplasia. death after ampullectomy. This was in the patient with severe liver cirrhosis who went into renal and liver failure postoperatively. Recurrences were identified in 3 of 29 patients after ampullectomy. Median followup time was 16 months (range 1 to 103 months). None of the four patients with high-grade dysplasia on final pathologic analysis have had evidence of recurrence. One recurrence was identified in a patient who refused a pancreaticoduodenectomy in the early postoperative period for carcinoma. This patient experienced a local recurrence at 8 months and subsequently underwent a pancreaticoduodenectomy. This patient had no evidence of recurrent disease after 76 months of followup. Another recurrence was identified in a 70-year-old patient with a villous adenoma who underwent ampullectomy. The patient was not compliant with followup endoscopic surveillance. A local recurrence was identified at 46 months, when the patient presented with jaundice. A palliative procedure was performed and the patient died from disease at 48 months after ampullectomy. Finally, a 59-year-old patient with cardiomyopathy and an ejection fraction of 15% underwent ampullectomy for a tubular adenoma. A local recurrence was identified at 6 months on scheduled endoscopy. The patient was not a candidate for pancreaticoduodenectomy because of severe comorbidities. The tumor eventually progressed to malignancy with metastases and the patient died from disease 35 months after initial treatment. Table 5. Postoperative Complications in Patients Undergoing Ampullectomy Complication n Wound infection 6 Pneumonia 3 Pancreatitis 3 Duodenal leak 2 Pancreatic or biliary fistula 2 Abdominal abscess 3 Postoperative transfusion 2 Acute renal failure 1 Delayed gastric emptying 1 Clostridium difficile colitis 1 Deep venous thrombosis 1 Death 1 DISCUSSION tous growths in the small bowel are among the most common small bowel neoplasms. With the increasing use of endoscopy and advancing age of the current population, they are being recognized with greater frequency. These tumors are most often identified in the proximal small bowel. 2 Management is more complicated when the tumors are located at the ampulla because indications for and experience with local resection of the ampulla are limited. Since Halsted s 4 first description of local resection of the ampulla for periampullary neoplasms in 1899, surgeons have debated the proper use of this less radical alternative to pancreaticoduodenectomy. The advantage of ampullectomy is related to the ability to remove early periampullary growths without the side effects of pancreaticoduodenectomy. Yet, experience with pancreaticoduodenectomy in tertiary treatment centers has expanded rapidly; the reported experience with ampullectomy is almost anecdotal. Uniform indications for ampullectomy have not been widely accepted. Although some have advocated ampullectomy for early stage (T1) ampullary invasive cancers, 9,10 most believe that this is an inadequate operation for invasive malignancy Ampullectomy for invasive cancer has its limitations in the ability to achieve negative margins and does not address possible lymph node metastases. In a recent report on ampullary malignancy, lymph node positivity rate was 42% in patients undergoing pancreaticoduodenectomy for T1 tumors. 12 Other authors have shown that 33% of patients had at least one risk factor for failure after ampullectomy for early ampullary cancer, including perineural invasion, lymphovascular invasion, and extensive common bile duct or pancreatic duct mucosal involvement. 13 Our study documented the recent use of ampullectomy at a tertiary cancer center with expertise in the management of periampullary tumors, and we have focused on preoper-

5 470 Grobmyer et al Ampullectomy for Benign Ampulla Neoplasms J Am Coll Surg ative workup and test results in these patients. In addition, we have carefully evaluated the accuracy of preoperative and intraoperative histologic evaluation of these tumors. Recurrence rates and complications of the ampullectomy procedure have been recorded. Ampullectomy is well tolerated, as demonstrated by this study. A pancreatic or biliary fistula was seen in two patients. Pancreatitis was seen in an additional three patients after ampullectomy. So, although complications do occur, they appear to be less frequent than for patients undergoing pancreaticoduodenectomy. 7 In addition, pancreaticoduodenectomy can be hazardous for early ampullary tumors because these operations have the highest potential for pancreatic fistula after pancreaticoduodenectomy. This is because most patients with early ampullary tumors will have soft pancreatic glands and small pancreatic ducts. These factors are associated with the highest leak rates after pancreaticoenteric anastomosis. 14,15 Only one patient, as demonstrated in this study, presented with pancreatitis or had severe pancreatic ductal dilation by CT, so these patients would be considered high risk for leakage after pancreaticoenterostomy. Clinicians are concerned that preoperative biopsy and intraoperative frozen sections are not accurate enough to exclude malignancy in ampullary tumors. Given that preoperative biopsy and intraoperative frozen sections are providing only a small sample of a larger lesion, the presence of invasive disease can be missed, so these methods may give a false sense of security. In fact, the presence of severe dysplasia on preoperative biopsy or intraoperative frozen section would make many surgeons advocate a pancreaticoduodenectomy. 9 In addition, there is no clear consensus on the management of ampullary tumors with high-grade dysplasia. Some fear that recurrence rates are unacceptably high in these patients. But in a report of eight patients undergoing ampullectomy for an adenoma with severe dysplasia, no recurrent disease was noted. 9 Similarly, in this study, no recurrences were noted in four patients undergoing ampullectomy in the presence of high-grade dysplasia, although recurrences were identified in two patients with adenoma without high-grade dysplasia. With these limited data, it does not seem that patients with high-grade dysplasia have any higher rates of recurrence, and it is difficult to determine which patients are at greatest risk. In general, there is an increased risk for recurrence after ampullectomy as compared with the more radical surgical approach of pancreaticoduodenectomy, and careful followup with endoscopic surveillance is recommended for all patients. Although advances have been made in the molecular characterization of ampullary tumors, differentiation between benign and malignant lesions at the ampulla remains a challenge. 16,17 Patients with benign tumors can present with abnormal liver function tests and occasionally, jaundice, as demonstrated in this study. Concomitant biliary ductal dilation is identified in some patients. But pancreatic ductal dilation or double duct dilation was not seen in the presence of a benign lesion. Esophagogastroduodenoscopy, as indicated by this study, was the most commonly used study for evaluation and workup of an ampullary mass. This test demonstrated the presence of a mass in all patients. During endoscopic ultrasonography lesions must be well sampled with multiple biopsies to rule out malignancy or premalignant changes such as high-grade dysplasia. If focal high-grade dysplasia is seen, ampullectomy should still be considered with careful intraoperative frozen section analysis. The patient must understand that a decision about final treatment would not be rendered until the permanent histologic sections are reviewed because deeper portions of the lesion, where invasive tumor is most likely found, may not be sampled in biopsies. Additionally, a representative frozen section taken intraoperatively may not find a focal area of invasion. In at least two patients in this study who had evidence of high-grade dysplasia, concordance of the preoperative and intraoperative frozen section biopsies with final histologic review allowed for avoidance of pancreaticoduodenectomy. In conclusion, ampullectomy is a safe procedure when performed in experienced centers. Indications for this procedure include benign and premalignant lesions at the ampulla. Preoperative biopsy and intraoperative frozen section analysis have limitations in the evaluation of patients who present with benign lesions at the ampulla. Decisions about treatment should be based on patterns of patient presentation and careful pathologic review of all biopsy specimens. After ampullectomy, patients are at a small increased risk for local recurrence compared with the risk after pancreaticoduodenectomy, in which no local recurrence would be anticipated for benign lesions. So, after ampullectomy for benign lesions, careful followup endoscopic evaluation is recommended. Author Contributions Study conception and design: Grobmyer, Vogel, Hochwald Acquisition of data: Grobmyer, Stasik, Draganov, Hemming, Hochwald Analysis and interpretation of data: Grobmyer, Stasik, Dixon, Hochwald Drafting of manuscript: Grobmyer, Dixon, Hochwald Critical revision: Hochwald Acknowledgment: We would like to acknowledge the editing assistance of Jason Cline in the preparation of this article.

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