Gastroenterology Hepatology

Ampullary and periampullary adenomas and carcinomas

How can I be sure that the patient has ampullary and periampullary adenomas and/or carcinomas?

Duodenal adenomas are mucosal neoplasms with malignant potential. While these lesions may present with symptoms, they are most commonly found incidentally during endoscopy for an unrelated reason. Duodenal adenomas can arise anywhere in the duodenum but occur most commonly in the ampullary or periampullary region of the second portion of the duodenum. Their appearance may be flat, sessile, and less likely to be pedunculated. When invasive cancer is present, they are more apt to present as fixed, friable, or ulcerated lesions.

Evaluation with a side-viewing duodenoscope is typically necessary to discriminate true ampullary from periampullary lesions. White light endoscopy is usually sufficient to demarcate the lesion's pit pattern and margin.

Most duodenal adenomas are sporadic (Figure 1). Duodenal adenomas are almost always uniformally seen associated with the genetic syndrome of familial adenomatous polyposis (FAP) or Gardner's syndrome. Peutz-Jeghers syndrome (PJS) is associated with nonadenomatous pedunculated hamartomatous polyps.

Figure 1

A large sporadic ampullary adenoma is seen in the second portion of the duodenum. This lesion was resected by endoscopic mucosal resection.

Ampullary and periampullary adenomas may progress to carcinoma. By convention, a duodenal adenoma is considered to represent low-grade dysplasia (LGD). Progression through high-grade dysplasia (HGD) to carcinoma, may be difficult to determine by any endoscopically distinguishable features.

A tabular or chart listing of features and signs and symptoms

What are the features, signs, and symptoms of ampullary and periampullary adenomas and carcinomas?

Ampullary and periampullary adenomas and carcinomas present with a wide clinical spectrum. Most patients with duodenal adenomas are asymptomatic. Ampullary tumors may present with biliary pain, fluctuating transaminases, jaundice, and/or pancreatitis. Gastrointestinal blood loss suggests progression to carcinoma. Duodenal obstruction is a feature of advanced disease.

Most commonly, duodenal adenomas are identified incidentally when upper endoscopy is completed for some other reason. Some ampullary adenomas will be observed to extend into the main pancreatic duct (PD) or the common bile duct (CBD); in these circumstances, patients may develop biliary obstruction and abdominal pain/cholastasis/cholangitis, or pancreatic duct obstruction and pancreatitis.

Patients with periampullary lesions are less commonly symptomatic; they may describe abdominal pain as a symptom but do not present with symptoms consistent with biliary duct or PD obstruction. Adenomas and/or carcinomas of either location can grow in size and cause obstruction of the duodenum. These patients may present with typical symptoms of small bowel obstruction, including bleeding, abdominal pain, nausea, or vomiting.

Specific subsets of patients have a higher risk of developing ampullary and periampullary adenomas, and these patients should be screened periodically with upper endoscopy; specifically, patients with FAP have a 20% chance of developing ampullary or periampullary adenomas. These patients are more likely to be asymptomatic at the time of presentation if enrolled in a screening program.

One series of patients discussed in a work published by Irani et al. in 2009 presented 150 patients with ampullary adenomatous lesions. Of these, 72 presented with cholestasis/cholangitis, 54 presented with abdominal pain, 51 had lesions discovered incidentally, 9 had pancreatitis, 7 had bleeding, and 28 presented with weight loss. In this series, 23 patients had FAP and all of these patients were asymptomatic.

How can I confirm the diagnosis?

Once an ampullary or periampullary lesion is identified, efforts should be made to characterize the location of the lesion in relation to the ampulla of Vater.

For lesions that are periampullary, evaluation should include determination of the location of the lesion, size of the lesion, and the extent of the lumen involved by the lesion. Lesions should be carefully examined to ensure they are distinct from the ampulla of Vater (Figure 2). Use of a duodenoscope, or side-viewing endoscope, is necessary to best visualize the lesion.

Figure 2

A large laterally spreading sporadic duodenal adenoma is seen in the second portion of the duodenum. An ERCP catheter is used to discern the margin of the lesion as distinct and separate from the ampulla of vater (arrow).

Lesions that are distinctly separated from the ampulla are treated differently in the evaluation from lesions that involve the ampulla. For periampullary lesions, biopsy should be taken at the time of initial evaluation to confirm diagnosis of adenoma and to determine degree of dysplasia. The diagnostic accuracy for biopsy ranges from 45% to 100% in the literature.

If biopsy is positive for HGD or adenocarcinoma, or endoscopic characteristics concerning for malignancy are visualized, further evaluation with endoscopic ultrasound (EUS) may be warranted to assist in determining the best treatment option. Endoscopic characteristics concerning for malignancy include friability, firmness, ulceration, puckering of the folds, bleeding, nonlifting sign with submucosal injection, size larger than 2 cm, or circumferential involvement at more than 50%.

Narrow band imaging (NBI) can be used to evaluate the lesion for alteration in the pit pattern to correspond with adenoma or carcinoma. EUS can reveal the extent of involvement, the depth of invasion (i.e., invasion into the muscularis propria), and the presence of associated lymph nodes or local invasion. EUS can also confirm that the lesion is distinct from the pancreatic-biliary tree. Some authors advocate that all lesions larger than 2 cm in size should undergo evaluation by EUS prior to treatment with endoscopic resection or surgery. EUS has been shown to be superior to CT, MRI, or transabdominal ultrasound for tumor staging. However, when endoscopic resection is planned, we no longer routinely use pre-resection EUS unless the lesion has features concerning for invasive carcinoma.

For lesions arising from the ampulla of Vater, evaluation should include endoscopic assessment of size and circumferential involvement. The lesion should be probed with closed forceps to assess its fixation or mobility. Forceps biopsies should also be obtained at the time of initial evaluation. Care should be taken to avoid biopsies at the pancreatic duct orifice to reduce the risk of procedure-associated pancreatitis.

It is recognized that forceps biopsies alone may underdiagnose the degree of dysplasia in bulky ampullary adenomas. Although biopsies after biliary sphincterotomy may increase accuracy of dysplasia detection, this practice is not advocated when endoscopic papillectomy is being considered.

EUS is important in the pretreatment evaluation of ampullary adenomas. EUS is highly accurate in the detection of invasive pancreatic cancer extension and for adenomatous extension into the CBD. Endoscopic retrograde cholangiopancreatography (ERCP) should also be undertaken at the time of planned endoscopic resection of an ampullary lesion. ERCP, in conjunction with EUS, is used to determine the extent of involvement of the CBD and the PD with adenomatous tissue. Extension of adenomatous tissue into the duct can present as irregularity in the CBD or as CBD or PD dilation.

Extension of tissue into the CBD or main PD determines the treatment options. Some clinicians propose that all lesions extending into the ductal system should be treated with surgical resection, whereas others propose that lesions with less than 1 cm extension may be amenable to endoscopic resection and ablation. Moreover, ERCP facilitates prophylactic PD stenting following endoscopic papillectomy. Removal of ampullary and nonampullary duodenal adenomas requires a high level of endoscopic expertise and experience.

Endoscopic biliary stent placement provides effective palliation for patients with ampullary cancers that are not amenable to endoscopic resection.

A diagnostic algorithm

Atthe first endoscopic evaluation, lesions should be determined to beampullary or periampullary, using duodenoscopy. Lesions should bebiopsied. Ampullary lesionsshould undergo EUS examination. This information is gathered todetermine whether treatment should be undertaken with endoscopicresection or surgical resection.

What other diseases, conditions, or complications should I look for in patients with ampullary/periampullary adenoma?

Major risk factors

Duodenal adenoma can be sporadic or they can be associated with genetic syndromes such as FAP or Gardener's syndrome. PJS is associated with nonadenomatous duodenal and other small bowel hamartomatous polyps. Patients in whom duodenal adenomas are discovered should be considered for colonoscopy.

Colonic polyps are universally seen in patients with FAP. Although studies have not convincingly established a relationship between the presence of a sporadic duodenal adenoma and an increased risk for colorectal neoplasia, a one-time colonoscopy is generally advocated for surveillance of colon cancer/colon polyps.

Commonly encountered complications

Duodenal adenomas should be resected endoscopically or surgically with complete eradication as the goal outcome. Without complete removal, these lesions have the potential for local recurrence. The natural history of duodenal adenomas has not been well studied. However, the pathogenesis of these lesions is similar to lesions of the colon, with a sequence from adenoma to HGD to carcinoma.

A recently published case series by Okada et al. (2011) followed patients prospectively after diagnosis of their index lesion. In this series, 43 lesions with LGD were followed prospectively; after a mean of 13.6 months of follow-up, 21% had progressed to HGD by biopsy and 5% had progressed to adenocarcinoma. Twenty-four lesions ultimately had treatment (endoscopic or surgical). Of the 11 that were diagnosed as HGD by biopsy, 5 revealed HGD at final histology and 6 revealed adenocarcinoma at final diagnosis. This demonstrates the potential of understaging that exists with biopsy alone.

What is the right therapy for the patient with ampullary/periampullary adenoma?

Patients with duodenal adenoma should be treated with endoscopic or operative resection with complete eradication as the goal.

In general, endoscopic management of ampullary or periampullary adenomas is favored over operative treatment because of the relative decrease in morbidity and mortality associated with this therapy. There are no standardized recommendations for determination of surgical versus endoscopic therapy.

In general, surgical resection of ampullary adenomas is indicated in patients with lesions that extend beyond 1 cm up into the CBD or main PD, in lesions that are larger than 4 cm or in lesions that involve more than 50% circumference of the lumen. Lesions with biopsy-demonstrated adenocarcinoma are generally considered for surgical therapy. Ampullary carcinomas and large ampullary adenomas deemed unfit for endoscopic curative therapy should undergo Whipple resection. Local surgical resection of ampullary tumors has been largely abandoned owing to high local recurrence rates.

Periampullary lesions are referred for surgery for similar findings: size larger than 4 cm, circumferential involvement of more than 50%, or the presence of HGD/carcinoma. Several small series have reported the use of endoscopic resection in early adenocarcinoma of the ampullary or periampullary region if the CBD and PD are not involved with tumor. Surgery for periampullary adenomas may involve laparotomy for transmural excision of lesion, segmental resection, or pancreaticoduodenectomy for complete eradication based on size and location of the lesion.

Patients with nonampullary lesions that do not have features of invasive carcinoma and encompass no more than 2/3 of the luminal circumference should be considered for endoscopic resection. The authors favor the use of submucosal injection with a methylene blue-tinted, diluted epinephrine solution of 1:10,000 concentration ( Figure 3). This technique allows the lesion to be raised onto a cushion of fluid separating the mucosa from the underlying muscular layer. The use of submucosal injection also allows evaluation for the "nonlifting sign."

Figure 3

Following piecemeal resection, the resection site base is stained by the methylene blue-tinted submucosal injectate.

Lesions that have persistent central depression or that fail to adequately raise on a bed of saline are concerning for cancer invasion and may prove unamenable to endoscopic resection. Subsequently, standard and mini-polypectomy snares are 1used to perform enbloc or, more often, piecemeal resection. En bloc resection is favored for lesions that are less than 2 cm in diameter. Piecemeal resection is generally required for lesions larger than 2 cm. Contact or noncontact thermal ablation may be used adjunctively to achieve complete eradication of small areas of residual tissue, although, in general, this practice is not favored by the authors' group.

It is optimal to make every effort to achieve complete eradication at the initial treatment session. Subsequent postresection scarring will make future efforts more difficult. Intravenous glucagon is administered to retard peristalsis thereby reducing the risk of the lesion being lost to the more distal small bowel. A retrieval net is used to acquire the resected specimens for submission to pathology. The optimal electrosurgical current for endoscopic resection of duodenal adenomas has not been determined. We use a pure coagulation current or an Endocut (ERBE®) mode.

Endoscopic papillectomy involves the complete excision of the papilla and all associated adenomatous tissue using endoscopic electrocautery snare techniques. Ideally, the lesion is resected en bloc much like the resection of a broad-based pedunculated polyp. Endoscopic papillectomy for ampullary adenoma is associated with a risk of postprocedure pancreatitis. To reduce this risk, the use of prophylactic pancreatic stents has been advocated. This practice is supported by one prospective randomized control trial that demonstrated a significantly lower rate of postprocedure pancreatitis in the group that received pancreatic stenting. We advocate this practice, and place a pancreatic stent immediately after the adenoma resection (Figure 4). The use of prophylactic pancreatic stenting has been shown to also reduce the risk of PD stenosis associated with this procedure.

Figure 4

At the conclusion of the procedure, a prophylactic pancreatic duct stent was placed (seen here). A clip was placed at the base of the resection site to achieve adqeuate hemostasis.

Endoscopic resection of duodenal and ampullary adenomas is associated with an increased risk of postprocedure bleeding. This can present acutely or in a delayed fashion from 12 hours to 12 days after the procedure. In order to minimize this risk, we generally observe patients with lesions larger than 2 cm in diameter for overnight observation in the hospital.

There is insufficient evidence to support the routine use of argon plasma coagulation to reduce the risk of postprocedure bleeding. Prophylactic clipping appears more effective and we employ this in selected patients, such as those who will be resuming anticoagulation or antiplatelet therapies.

What treatment options are effective?

In a large number of retrospective case series, endoscopic therapy has been shown to be efficacious for patients with periampullary and ampullary adenomas. In the authors' own recently described experience, 36 patients with periampullary sporadic adenomas were evaluated for endoscopic resection. Three patients were referred directly for surgery. Of the remaining 33, complete eradication was achieved in 23 patients (69.7%). Several series describing resection of ampullary lesions demonstrate similar results: complete eradication rates have been reported to range form 46% to 92%.

Predictors of endoscopic success have not been well delineated in the literature. In our case series of patients undergoing periampullary adenoma resection, use of en bloc resection, snare excision, and submucosal injection were statistically associated with complete eradication. Patient age of more than 70 years, application of APC ablation, and increasing size of lesion were negatively correlated with complete resection.

What is the most effective initial therapy?

In general, endoscopic therapy is preferred to surgical resection because of the decreased rates of morbidity and mortality. In the literature, successful eradication has been reported in 46% to 92% of patients with one or multiple endoscopic procedures.

LIsting of usual therapeutic options, including guidelines for use, along with expected result of therapy.

What therapy is best if initial therapy fails, including definitions of failure?

Patients who are unsuccessfully eradicated by endoscopic resection should be evaluated for surgical therapy of lesions because of the known risk of lesion progression to malignancy. Failure is defined as the inability to demonstrate complete eradication of the duodenal adenomatous lesion. We employ argon plasma beam coagulation to eradicate residual or recurrent flat adenomatous tissue that is unamenable to snare resection in selective cases. Last, we have opted to survey selected patients with lesions that are unamenable to endoscopic therapy but deemed unfit for operative resection.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

N/A

Listing of these, including any guidelines for monitoring side effects.

Complications of endoscopic resection of ampullary or periampullary lesions can include bleeding, perforation, pancreatitis, or cholangitis in the acute setting. Delayed complications can include papillary stenosis. Physicians should be vigilant in monitoring for these possible complications.

Complication rates for bleeding have been reported in 2% to 13% of patients after EMR. In patients in whom bleeding occurs, resuscitation is the first line of therapy. Although bleeding tends to stop spontaneously, repeat endoscopy should be undertaken when there is evidence of ongoing or recurrent bleeding. Hemostasis should be initiated with epinephrine injection and/or clips. We favor the use of ephinephrine injection and clips over bipolar electrocautery in this setting to minimize additional complications of perforation or transmural burn at a recent resection site.

Pancreatitis has been reported in up to 8% to 15% of patients following endoscopic papillectomy. To minimize this risk, in our practice we place prophylactic pancreatic stents following ampullary resection. This practice has been shown to reduce the incidence and severity of pancreatitis. When pancreatic stents are placed, patients need to return within 1 to 2 weeks after resection for repeat endoscopy and pancreatic stent removal.

Alternatively, a "barbless" stent may be used to allow spontaneous migration and elimination. In the latter case, a follow up abdominal radiograph should be obtained to document spontaneous migration. Perforation has been reported in 0% to 4% of patients.

Early recognition and aggressive nonoperative managment with NPO, IV antibiotics, and NG aspiration may be effective. However, surgical intervention is required for those patients exhibiting septic physiology. Papillary stenosis can present as a delayed complication and can be seen in up to 8% of ampullary resections. This complication may present with obstructive symptoms and is treated with sphincterotomy, stent placement, or balloon dilation – depending on the degree of stenosis.

How should I monitor the patient with ampullary/periampullary adenoma?

The timing of follow-up endoscopy after endoscopic resection for ampullary or periampullary adenoma is individualized and based on histopathological findings and the endoscopist's degree of certainty that the lesion has undergone curative resection. Local residual/recurrent disease is seen more commonly after resection of larger lesions (>25% of the luminal circumference) and those requiring piecemeal resection.

Initial endoscopy is generally recommended 6 weeks to 6 months after the initial resection procedure: patients with large lesions that required piecemeal resection are favored to be reexamined at short intervals, while patients with en bloc resection can often be reexamined at longer intervals. The initial endoscopy is to confirm complete eradication of adenomatous tissue. Patients with HGD or carcinoma should also have repeat endoscopy at a short intervals.

After complete eradication is documented, patients can return at intervals of 6 to 12 months for at least 2 years. There are no specific guidelines directing surveillance interval. Subsequent intervals of endoscopies can be extended therafter.

After surgical therapy, patients with sporadic ampullary or periampullary lesions require no further surveillance.

Patients with ampullary or periampullary adenomas in the setting of FAP are approached differently than those with sporadic lesions. Because adenoma development and progression is generally relentless in this patient population, endoscopic papillectomy is reserved by the authors for selected patients with symptomatic ampullary tumors who wish to defer Whipple resection for the time being. When feasible, the authors perform EMR of FAP-related duodenal adenomas when these approach 1 cm in size. When the duodenum is overrun with multiple large sessile and flat lesions, surveillance biopsies is performed to detect progression to HGD as the trigger for operative resection. After surgical resection, patients with FAP may develop recurrent or remote lesions within the segment of bowel continuously exposed to direct flow of bile. Even after surgical therapy, these patients should continue in a surveillance program.

What's the evidence?

Kedia, P, Brensinger, C, Ginsberg, G. " Endoscopic predictors of successful endoluminal eradication in sporadic duodenal adenomas and its acute complications". Gastrointest Endosc. vol. 72. 2010. pp. 1297-301.

(This retrospective study describes our experience with duodenal adenomas and discusses characteristics that predict the likelihood of successful eradication after endoscopic resection.)

Adler, D, Qureshi, W, Davila, R. "The role of endoscopy in ampullary and duodenal adenomas". Gastrointest Endosc. vol. 64. 2006. pp. 849-54.

(This article provides a general review of the approach to periampullary and ampullary adenomas. This review represents the ASGE's recommendations.)

Irani, S, Arai, A, Kamran, A. "Papillectomy for ampullary neoplasm: results of a single referral center over a 10-year period". Gastrointest Endosc . vol. 70. 2009. pp. 923-32.

(This study describes a cohort of patients followed prospectively and treated for ampullary adenomas. The cohort in this study demonstrates the varioius clinical presentations in patients with duodenal lesions.)

Lee, SY, Jang, KT, Lee, KT. "Can endoscopic resection be applied for early stage ampulla of Vater cancer?". Gastrointest Endosc. vol. 63. 2006. pp. 783-8.

(This study describes one group's experience with endoscopic resection of lesions that extend less than 1 cm into the CBD or PD.)

Han, J, Kim, MH. "Endoscopic papillectomy for adenomas of the major duodenal papilla". Gastrointest Endosc. vol. 63. 2006. pp. 292-301.

(This review discusses indications, techniques, and outcomes of endoscopic and surgical papillectomy for ampullary adenomas.)

Cannon, ME, Carpenter, SL, Elta, GH. "EUS compared with CT, magnetic resonance imaging, and angiography and the influence of biliary stenting on staging accuracy of ampullary neoplasms". Gastrointest Endosc. vol. 50. 1999. pp. 27-33.

(This study demonstrates the staging accuracy of EUS compared to CT and MRI and indicates that accuracy decreases when a biliary stent is in place)

Okada, K, Fujisaki, J, Kasuga, A. "Sporadic nonampullary duodenal adenoma in the natural history of duodenal cancer: a study of follow-up surveillance". Am J Gastroenterol. 2011. pp. 357-64.

(This study describes one cohort of patients followed prospectively and discusses the possible understaging that can occur with biopsy alone.)

Harewood, GC, Pochron, NL, Gostout, CJ. "Prospective, randomized, controlled trial of prophylactic pancreatic stent placement for endoscopic snare excision of the duodenal ampulla". Gastrointest Endosc. vol. 62. 2005. pp. 367-70.

(This study describes the only prospective randomized control trial that evaluates prophylactic PD stent placement after ampillectomy to minimize postprocedure pancreatitis.)
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