The limited accuracy of endoscopic biopsy in detecting high-grade dysplasia or adenocarcinoma within ampullary adenoma or dysplasia has been reported. The natural history of ampullary dysplasia is also unclear, and there are no established guidelines to determine which patients with ampullary dysplasia require resection versus surveillance endoscopy. DNA flow cytometry was performed on 47 ampullary biopsies with low-grade dysplasia, 18 high-grade dysplasia, and 23 negative for dysplasia, as well as 11 cases of ampullary adenocarcinoma. Abnormal DNA content (aneuploidy or elevated 4N fraction > 6%) was identified in 9 (82%) of adenocarcinoma, 13 (72%) of high-grade dysplasia, 7 (15%) of low-grade dysplasia, and none (0%) of non-dysplastic mucosa. One-, 2-, and 7-year detection rates of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with abnormal DNA content were 57%, 86%, and 88%, respectively, whereas low-grade dysplasia patients in the setting of normal DNA content had 1-, 2-, and 7-year detection rates of 10%, 10%, and 10%, respectively. The univariate and multivariate hazard ratios (HRs) for subsequent detection of high-grade dysplasia or adenocarcinoma in low-grade dysplasia patients with DNA content abnormality were 16.8 (p = <0.01) and 9.8 (p = <0.01), respectively. Among the 13 high-grade dysplasia patients with DNA content abnormality, 5 patients (38%) were subsequently found to have adenocarcinoma within a mean follow-up time of 3 months, whereas only 1 (20%) of the remaining 5 patients in the setting of normal DNA content developed adenocarcinoma in a month (HR = 2.6, p = 0.39). The overall 1- and 2-year detection rates of adenocarcinoma in all high-grade dysplasia patients (regardless of flow cytometric results) were 34% (95% confidence interval = 16–63%) and 47% (95% confidence interval = 23–79%), respectively. In conclusion, the majority of low-grade dysplasia patients (86%) in the setting of abnormal DNA content developed high-grade dysplasia or adenocarcinoma within 2 years and thus may benefit from resection, whereas those with normal DNA content may be followed with surveillance endoscopy. The presence of DNA content abnormality can also confirm a morphologic suspicion of high-grade dysplasia, which should be managed with resection, as nearly 50% of the high-grade dysplasia patients were found to have adenocarcinoma within 2 years.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $52.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Offerhaus GJ, Giardiello FM, Krush AJ, Booker SV, Tersmette AC, Kelley NC, et al. The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology. 1992;102:1980–2.
Chathadi KV, Khashab MA, Acosta RD, Chandrasekhara V, Eloubeidi MA, Faulx AL, et al. The role of endoscopy in ampullary and duodenal adenomas. Gastrointest Endosc. 2015;82:773–81.
Stolte M, Pscherer C. Adenoma-carcinoma sequence in the papilla of Vater. Scand J Gastroenterol. 1996;31:376–82.
van Stolk R, Sivak MVJ, Petrini JL, Petras R, Ferguson DR, Jagelman D. Endoscopic management of upper gastrointestinal polyps and periampullary lesions in familial adenomatous polyposis and Gardner’s syndrome. Endoscopy. 1987;19:19–22.
Martin JA, Haber GB. Ampullary adenoma: clinical manifestations, diagnosis, and treatment. Gastrointest Endosc Clin N Am. 2003;13:649–69.
Burke CA, Beck GJ, Church JM, van Stolk RU. The natural history of untreated duodenal and ampullary adenomas in patients with familial adenomatous polyposis followed in an endoscopic surveillance program. Gastrointest Endosc. 1999;49:358–64.
Hirota WK, Zuckerman MJ, Adler DG, Davila RE, Egan J, Leighton JA, et al. ASGE guideline: the role of endoscopy in the surveillance of premalignant conditions of the upper GI tract. Gastrointest Endosc. 2006;63:570–80.
Matsumoto T, Iida M, Nakamura S, Hizawa K, Yao T, Tsuneyoshi M, et al. Natural history of ampullary adenoma in familial adenomatous polyposis: reconfirmation of benign nature during extended surveillance. Am J Gastroenterol. 2000;95:1557–62.
Kim HN, Kim KM, Shin JU, Lee JK, Lee KT, Lee KH, et al. Prediction of carcinoma after resection in subjects with ampullary adenomas on endoscopic biopsy. J Clin Gastroenterol. 2013;47:346–51.
Kim JH, Kim JH, Han JH, Yoo BM, Kim MW, Kim WH. Is endoscopic papillectomy safe for ampullary adenomas with high-grade dysplasia? Ann Surg Oncol. 2009;16:2547–54.
Di Giorgio A, Alfieri S, Rotondi F, Prete F, Di Miceli D, Ridolfini MP, et al. Pancreatoduodenectomy for tumors of Vater’s ampulla: report on 94 consecutive patients. World J Surg. 2005;29:513–8.
Cahen DL, Fockens P, de Wit LT, Offerhaus GJ, Obertop H, Gouma DJ. Local resection or pancreaticoduodenectomy for villous adenoma of the ampulla of Vater diagnosed before operation. Br J Surg. 1997;84:948–51.
Tran TC, Vitale GC. Ampullary tumors: endoscopic versus operative management. Surg Innov. 2004;11:255–63.
Mendonça EQ, Bernardo WM, Moura EG, Chaves DM, Kondo A, Pu LZ, et al. Endoscopic versus surgical treatment of ampullary adenomas: a systematic review and meta-analysis. Clinics. 2016;71:28–35.
Chini P, Draganov PV. Diagnosis and management of ampullary adenoma: the expanding role of endoscopy. World J Gastrointest Endosc. 2011;3:241–7.
Posner S, Colletti L, Knol J, Mulholland M, Eckhauser F. Safety and long-term efficacy of transduodenal excision for tumors of the ampulla of Vater. Surgery. 2000;128:694–701.
Ceppa EP, Burbridge RA, Rialon KL, Omotosho PA, Emick D, Jowell PS, et al. Endoscopic versus surgical ampullectomy: an algorithm to treat disease of the ampulla of Vater. Ann Surg. 2013;257:315–22.
van der Wiel SE, Poley JW, Koch AD, Bruno MJ. Endoscopic resection of advanced ampullary adenomas: a single-center 14-year retrospective cohort study. Surg Endosc. 2018;33:1180–8.
Catalano MF, Linder JD, Chak A, Sivak MVJ, Raijman I, Geenen JE, et al. Endoscopic management of adenoma of the major duodenal papilla. Gastrointest Endosc. 2004;59:225–32.
Kang SH, Kim KH, Kim TN, Jung MK, Cho CM, Cho KB, et al. Therapeutic outcomes of endoscopic papillectomy for ampullary neoplasms: retrospective analysis of a multicenter study. BMC Gastroenterol. 2017;17:69.
Attila T, Parlak E, Alper E, Dişibeyaz S, Çiçek B, Ödemiş B. Endoscopic papillectomy of benign ampullary lesions: Outcomes from a multicenter study. Turk J Gastroenterol. 2018;29:325–34.
Hong S, Song KB, Lee YJ, Park KM, Kim SC, Hwang DW, et al. Transduodenal ampullectomy for ampullary tumors—single center experience of consecutive 26 patients. Ann Surg Treat Res. 2018;95:22–8.
Laleman W, Verreth A, Topal B, Aerts R, Komuta M, Roskams T, et al. Endoscopic resection of ampullary lesions: a single-center 8-year retrospective cohort study of 91 patients with long-term follow-up. Surg Endosc. 2013;27:3865–76.
Patel R, Davitte J, Varadarajulu S, Wilcox CM. Endoscopic resection of ampullary adenomas: complications and outcomes. Dig Dis Sci. 2011;56:3235–40.
Grobmyer SR, Stasik CN, Draganov P, Hemming AW, Dixon LR, Vogel SB, et al. Contemporary results with ampullectomy for 29 “benign” neoplasms of the ampulla. J Am Coll Surg. 2008;206:466–71.
Ryan DP, Schapiro RH, Warshaw AL. Villous tumors of the duodenum. Ann Surg. 1986;203:301–6.
Yamaguchi K, Enjoji M, Kitamura K. Endoscopic biopsy has limited accuracy in diagnosis of ampullary tumors. Gastrointest Endosc. 1990;36:588–92.
Elek G, Gyôri S, Tóth B, Pap A. Histological evaluation of preoperative biopsies from ampulla vateri. Pathol Oncol Res. 2003;9:32–41.
Lee SY, Jang KT, Lee KT, Lee JK, Choi SH, Heo JS, et al. Can endoscopic resection be applied for early stage ampulla of Vater cancer? Gastrointest Endosc. 2006;63:783–8.
Allard F, Goldsmith JD, Ayata G, Challies TL, Najarian RM, Nasser IA, et al. Intraobserver and interobserver variability in the assessment of dysplasia in ampullary mucosal biopsies. Am J Surg Pathol. 2018;42:1095–100.
Howe JR, Klimstra DS, Cordon-Cardo C, Paty PB, Park PY, Brennan MF. K-ras mutation in adenomas and carcinomas of the ampulla of vater. Clin Cancer Res. 1997;3:129–33.
Scarpa A, Di Pace C, Talamini G, Falconi M, Lemoine NR, Iacono C, et al. Cancer of the ampulla of Vater: chromosome 17p allelic loss is associated with poor prognosis. Gut. 2000;46:842–8.
Chung CH, Wilentz RE, Polak MM, Ramsoekh TB, Noorduyn LA, Gouma DJ, et al. Clinical significance of K-ras oncogene activation in ampullary neoplasms. J Clin Pathol. 1996;49:460–4.
Park SH, Kim YI, Park YH, Kim SW, Kim KW, Kim YT, et al. Clinicopathologic correlation of p53 protein overexpression in adenoma and carcinoma of the ampulla of Vater. World J Surg. 2000;24:54–9.
Sato T, Konishi K, Kimura H, Maeda K, Yabushita K, Tsuji M, et al. Adenoma and tiny carcinoma in adenoma of the papilla of Vater—p53 and PCNA. Hepatogastroenterology. 1999;46:1959–62.
Younes M, Riley S, Genta RM, Mosharaf M, Mody DR. p53 protein accumulation in tumors of the ampulla of Vater. Cancer. 1995;76:1150–4.
Takashima M, Ueki T, Nagai E, Yao T, Yamaguchi K, Tanaka M, et al. Carcinoma of the ampulla of Vater associated with or without adenoma: a clinicopathologic analysis of 198 cases with reference to p53 and Ki-67 immunohistochemical expressions. Mod Pathol. 2000;13:1300–7.
Choi WT, Tsai JH, Rabinovitch PS, Small T, Huang D, Mattis AN, et al. Diagnosis and risk stratification of Barrett’s dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue. Gut. 2018;67:1229–38.
Tsai JH, Rabinovitch PS, Huang D, Small T, Mattis AN, Kakar S, et al. Association of aneuploidy and flat dysplasia with development of high-grade dysplasia or colorectal cancer in patients with inflammatory bowel disease. Gastroenterology. 2017;153:1492–5.
Wen KW, Rabinovitch PS, Wang D, Huang D, Mattis AN, Choi WT. Utility of DNA flow cytometric analysis of paraffin-embedded tissue in the risk stratification and management of ‘Indefinite for Dysplasia’ in patients with inflammatory bowel disease. J Crohns Colitis. 2019;13:472–81.
Wen KW, Rabinovitch PS, Huang D, Mattis AN, Lauwers GY, Choi WT. Use of DNA flow cytometry in the diagnosis, risk stratification, and management of gastric epithelial dysplasia. Mod Pathol. 2018;31:1578–87.
Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000;47:251–5.
Shankey TV, Rabinovitch PS, Bagwell B, Bauer KD, Duque RE, Hedley DW, et al. Guidelines for implementation of clinical DNA cytometry. International Society for Analytical Cytology. Cytometry. 1993;14:472–7.
Rabinovitch PS, Longton G, Blount PL, Levine DS, Reid BJ. Predictors of progression in Barrett’s esophagus III: baseline flow cytometric variables. Am J Gastroenterol. 2001;96:3071–83.
Rabinovitch PS. Practical considerations for DNA content and cell cycle analysis. In: Bauer KD, Duque RE, Shankey TV, eds. Clinical flow cytometry: principles and applications. Baltimore: Williams and Wilkins; 1992. p. 117–42.
Shyr YM, Su CH, Wu LH, Li AF, Chiu JH, Lui WY. DNA ploidy as a major prognostic factor in resectable ampulla of Vater cancers. J Surg Oncol. 1993;53:220–5.
Seewald S, Omar S, Soehendra N. Endoscopic resection of tumors of the ampulla of Vater: how far up and how deep down can we go? Gastrointest Endosc. 2006;63:789–91.
Yoon SM, Kim MH, Kim MJ, Jang SJ, Lee TY, Kwon S, et al. Focal early stage cancer in ampullary adenoma: surgery or endoscopic papillectomy? Gastrointest Endosc. 2007;66:701–7.
Meneghetti AT, Safadi B, Stewart L, Way LW. Local resection of ampullary tumors. J Gastrointest Surg. 2005;9:1300–6.
Heidecke CD, Rosenberg R, Bauer M, Werner M, Weigert N, Ulm K, et al. Impact of grade of dysplasia in villous adenomas of Vater’s papilla. World J Surg. 2002;26:709–14.
Achille A, Baron A, Zamboni G, Di Pace C, Orlandini S, Scarpa A. Chromosome 5 allelic losses are early events in tumours of the papilla of Vater and occur at sites similar to those of gastric cancer. Br J Cancer. 1998;78:1653–60.
Achille A, Biasi MO, Zamboni G, Bogina G, Iacono C, Talamini G, et al. Cancers of the papilla of vater: mutator phenotype is associated with good prognosis. Clin Cancer Res. 1997;3:1841–7.
Achille A, Scupoli MT, Magalini AR, Zamboni G, Romanelli MG, Orlandini S, et al. APC gene mutations and allelic losses in sporadic ampullary tumours: evidence of genetic difference from tumours associated with familial adenomatous polyposis. Int J Cancer. 1996;68:305–12.
Scarpa A, Capelli P, Zamboni G, Oda T, Mukai K, Bonetti F, et al. Neoplasia of the ampulla of Vater. Ki-ras and p53 mutations. Am J Pathol. 1993;142:1163–72.
Scarpa A, Zamboni G, Achille A, Capelli P, Bogina G, Iacono C, et al. ras-family gene mutations in neoplasia of the ampulla of Vater. Int J Cancer. 1994;59:39–42.
This study was funded by the University of California at San Francisco Department of Pathology.