Format for Manuscript Submission: Review

Name of Journal: World Journal of Methodology

Manuscript Type: REVIEW

Endoscopic management of adenomatous ampullary lesions

Espinel J et al. Ampullary lesions

Jesús Espinel, Eugenia Pinedo, Vanesa Ojeda, Maria Guerra del Rio

Jesús Espinel, Department of Digestive Diseases, Hospital Universitario de León,

León 24071, Spain

Eugenia Pinedo, Department of Radiodiagnosis, Hospital Universitario de León,

León 24071, Spain

Vanesa Ojeda, Department of Digestive Diseases, Hospital Universitario Dr. Negrín,

Las Palmas de Gran Canaria 35012, Spain

Maria Guerra del Rio, Consultant Gastroenterologist, Burton Hospitals NHS

foundation trust, Burton on Trent DE13 ORB, United Kingdom

Author contributions: Espinel J wrote the paper; Pinedo E, Ojeda V and Guerra del
Rio M perfomed the collected the data.

Supported by

Corresponding author: Jesús Espinel, MD, Department of Digestive Diseases,

Hospital Universitario de León, Altos de Nava S/N, León 24071, Spain.
[email protected]
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Abstract
Lesions of the ampulla of Vater represent an uncommon group of gastrointestinal
malignancies. The majority of lesions of the ampulla of Vater are either adenomas or
adenocarcinomas. Ampullary lesions are often incidental findings. Accurate
preoperative diagnosis and staging of ampullary tumors is imperative for predicting
prognosis and determining the most appropriate therapeutic approach. Endoscopic
ampullectomy is a safe and efficacious therapeutic procedure that can obviate the
need for potentially major surgical intervention. This review will provide the
framework for the diagnosis and management of ampullary lesions from the
perspective of the practicing gastroenterologist. Strategies for safe and successful
endoscopic ampullectomy with a focus on accurate preoperative diagnosis and
staging, resection technique, and management of complications are presented.

Key words: Ampullary adenoma; Papillary tumors; Endoscopic ampullectomy;

Endoscopic ultrasound; Pancreatitis

Core tip: Adenomatous ampullary lesions are rare. Endoscopic retrograde

cholangiopancreatography and endoscopic ultrasound (EUS) have changed the
management of patients with these lesions. Endoscopic ampullectomy is a technique
that has revolutionized the treatment of these lesions avoiding potential
complications of surgery. We herein discuss the epidemiology, the role of EUS in the
local staging and the role of endoscopy in the treatment of the adenomatous
ampullary neoplasms.

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INTRODUCTION
The anatomy of the ampulla of Vater is complex. Ampullary adenomas are an
uncommon group of gastrointestinal malignances. With the advances in
esophagogastroduodenoscopy and ultrasonography, detection of ampullary
neoplasms has increased. Most periampullary lesions are malignant tumors
appearing from the ampulla, duodenum, or pancreas. Benign neoplasms entail in
this region only < 10% of neoplasms[1-3]. Advances in endoscopic retrograde
cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) have changed
the clinical management of these patients. Endoscopic ampullectomy may be
considered in patients with smaller lesions that do not contain invasive carcinoma,
and in patients who are poor surgical candidates[4-6]. Many series have reported low
morbidity and mortality with endoscopic therapy[4,7-19]. Detailed preoperative
assessment and staging is needed in other to decide on the best therapeutic option.
We review the epidemiology, the role of EUS, ERCP and endoscopy in the approach
of ampullary neoplasms.

EPIDEMIOLOGY
Ampullary neoplasms comprise several lesions: adenoma, adenocarcinoma,
adenoendocrine carcinoma, small cell carcinoma, adenosquamous carcinoma, and
undifferentiated carcinoma[20]. Adenomas or adenocarcinomas representing > 95% of
these lesions[21,22]. Ampullary adenomas (AA) are benign lesions but, can potencially
develop into ampullary carcinomas in a comparable progression to that of colorectal
cancer[2,3,23-29]. Ampullary adenomas can be sporadic or in the context of a familial
polyposis syndromes [e.g., familial adenomatous polyposis (FAP)]. FAP is a risk
factor; 80 percent of affected patients develop duodenal adenomas, which are often
multiple[30]. In this polyposis syndrome, the lifetime incidence of peri-ampullary
adenomas is 50%-100%. The prevalence of AA has increased in the last years with the
extensive availability of endoscopy.

CLINICAL MANIFESTATIONS

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Ampullary lesions are often found incidentally on cross-sectional imaging or by
endoscopic examination. Presenting symptoms are usually non-specific, reflecting
biliary or pancreatic obstruction. The most common presentation is with painless
jaundice, which is present in 50%-75% of patients[21,31-34]. Cholangitis or acute
pancreatitis are rare manifestations[35-38]. Nausea, vomiting, biliary colic, and weight
loss may also occur[21,33].

ACCURATE PREOPERATIVE DIAGNOSIS AND STAGING

Accurate preoperative diagnosis and staging is critical to decide on the best
treatment option and establish a prognosis.

Endoscopy
The best endoscopic examination of the papilla of Vater is performed with a side-
viewing endoscope[20]. This endoscope allows an adequate assessment of the
morphological features of the lesion. Thus the following features are suggestive of
benign disease: (1) a regular margin; (2) absence of ulceration or spontaneous
bleeding; and (3) a soft consistency[39]. Furthermore, the side-viewing endoscope
enables an easy acquisition of tissue by biopsy, at the time of procedure. However,
on this respect, we know that sensitivity with forceps biopsies for demonstrating the
presence of adenoma is > 90%; this is lower for adenocarcinoma, and there is up to
30% of miss diagnosis[11,40-42]. Thus, a negative histological diagnosis of carcinoma on
endoscopic biopsy of an ampullary adenoma does not exclude a possible focus of
adenocarcinoma[42-47]. The accuracy of endoscopic biopsies can be enhanced when
additional techniques are employed. Thus, taking biopsies several days after
sphincterotomy[48], and taking at least six biopsies, minimizes the chance of false
negative results[49] . Despite its gaps, endoscopic forceps biopsy is the mainstay of
pre-excisional histological assessment in lesions of the ampulla. However, we ought
to remember that resection of all ampullary adenomas might be the best approach for
excluding the presence of carcinoma.

Endoscopic retrograde cholangiopancreatography

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ERCP has a central role in the staging and management of obstructive jaundice in
ampullary adenomas. Adenoma ingrowth into the pancreatic or biliary ducts does
not always indicate malignancy, but may hinder endoscopic excision and
considerably decreases the chance of complete endoscopic resection. ERCP at the
time of endoscopic papillectomy permits: (1) evaluate the intraductal extension; (2)
the placement of a pancreatic stent in order to reduce the risk of pancreatitis; and (3)
deploy, if required, a biliary duct stent for the palliation of obstructive jaundice.

Endoscopic ultrasound
EUS, in conjunction with ERCP, allows to assess for infiltration of the periampullary
wall layers and pancreatobiliary ducts but, it does not have to be universally
incorpored into the diagnostic evaluation of an ampullary adenoma[45,50-57]. The use
of EUS in the assessment of ampullary adenomas is undefined. There is no consensus
on the requirement or not for EUS prior to consideration of treatment on all patients
with ampullary adenomas. It has been suggested by some experts that EUS is not
required if the lesion is less than 1 cm in diameter or there are no endoscopic signs to
suggest malignancy[58]. Others claim that, if accessible, EUS testing ought to be taken
into consideration prior to endoscopic or surgical resection[59]. EUS has been reported
to be of help in recognizing non-invasive lesions amenable to local resection, but as
yet there are no preoperative test which are as accurate as clinical judgment and
intraoperative pathological diagnosis[45,60]. A recent retrospective review concluded
that EUS is useful in predicting the depth of mucosal invasion in the preoperative
evaluation of suspected peri-ampullary and duodenal adenomas (specificity: 88%;
negative predictive value: 90%)[53]. However, EUS is an invasive technique, operator
dependent, with different rates of over-diagnosis and under-diagnosis. In this
context, peritumoral inflammatory changes can lead to over-staging and likewise
focal pancreatic infiltration to under-staging[61,62]. A recent meta-analisis of 14 studies
and a systematic review, concluded that the results obtained by EUS were
comparable to the histological results with moderate strength of agreement in the
following: preoperative staging of papillary neoplasm, predicting lymph node
involvement and tumor invasion[63]. The modest EUS sensitivity (77%) and specificity
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(78%) in predicting T1 neoplasms makes it not optimal in choosing the right patients
for endoscopic papillectomy. EUS sensitivity and specificity for detecting nodal
invasion was 70% and 74%, respectively. We believe, as other authors that if the
clinical suspicion for invasive carcinoma is low (e.g., absence of jaundice, endoscopic
features of noncancerous lesion), and the lesion appears amenable to endoscopic
resection, then EUS may not impact the endoscopist’s decision to stage the lesion via
ampullectomy. Few studies have been reported comparing efficacy of EUS and
intraductal ultrasound (IDUS) for ampullary neoplasms[54,60,64]. IDUS was superior to
EUS in terms of tumor visualization and staging (staging accuracy: 78%-93%).
Therefore, IDUS can be particularly appropriate in deciding which patients should
undergo endoscopic ampullectomy. However, the availability of this technique is
limited and therefore the number of patients undergoing IDUS is small.

Magnetic resonance imaging and computed tomography

Magnetic resonance imaging (MRI) and computed tomography (CT) use is limited to
staging of know ampullary cancers, for nodal staging and metastatic evaluation. CT
is less precise than EUS for T staging of ampullary cancer[56,65].

ENDOSCOPIC AMPULLECTOMY
Patients diagnosed with an ampullary adenoma have three treatment options:
pancreaticoduodenectomy (Whipple procedure), surgical local excision (surgical
ampullectomy), or endoscopic ampullectomy. There are no clear guidelines about the
surgical or endoscopic management of ampullary adenomas and, if they should
undergo postprocedure surveillance[66]. Surgical excision is typically recommended
for patients with larger lesions, lesions that contain carcinoma, lesions with lymph
node involvement on preprocedure imaging, or for patients who do not have access
to an experienced endoscopist in ampullectomy. Pancreaticoduodenectomy is more
likely to achieve complete excision compared with local excision, but it is associated
with higher operative morbidity and mortality rates (25%-65% and 0%-10%,
respectively)[67,68]. Perioperative mortality rates were lowest (< 4%) in centers with a
high procedure volume. Surgical ampullectomy has lower morbidity and mortality,
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but has the disadvantage of having more recurrence rate. Randomized trials
comparing surgical ampullectomy with pancreaticoduodenectomy have not been
performed. Endoscopic ampullectomy was first described in 1983 by Suzuki et al[59]
and ten years later Binmoeller et al[4] described a considerable case series. More
recently, many other series have reported low morbidity and mortality with
endoscopic therapy[7-19]. However, the role of endoscopic ampullectomy is still
debatable and it is largely performed only in reference hospitals with skill in
therapeutic endoscopy. Endoscopic ampullectomy may be considered in smaller
lesions (< 30 mm) that do not contain carcinoma and in patients with severe diseases.
Lesions with endoscopic characteristics suggestive of posible malignancy (e.g.,
nonlifting, firmness, ulceration, friability) should be offered surgical resection[6].

ENDOSCOPIC AMPULLECTOMY TECHNIQUE

General principles
Endoscopic ampullectomy is a therapeutic modality which must be undertaken by
an endoscopist with enough training and expertise. The goal with ampullary
adenomas is for total en-bloc removal of the neoplasm. Initially, the endoscopist must
determine whether resection of the entire lesion in one piece (“en bloc”) is feasible
and locate the margins of the lesion. This method has several advantages: (1) it
increases the likelihood of complete removal; (2) it provides clear margins for
histopathologic evaluation; and (3) it reduces the procedure time. However, en bloc
excision may not be technically feasible if the adenoma is of a large size, and/or there
is a limited endoscopic accessibility. Piecemeal excision is usually reserved for these
cases, frequently with adjuvant ablative therapy[69]. It has been postulated that this
technique can reduce recurrence rates, bleeding and perforation. However,
comparative trials are lacking[13] (Figure 1).

Submucosal lifting
The role of submucosal injection of saline, which may be combined with epinephrine
or methylene blue before ampullectomy, is controversial[6,62,66]. Epinephrine and
methylene blue may help minimize bleeding and enhance endoscopic visualization
7 / 26
of the lesions margins, respectively[13]. Local saline injection may increase technical
success and decrease complications similar to mucosectomy[13,70]. However, this
technique is not recommended by other authors because submucosal saline injection
may involve certain disadvantages: (1) the ampullary lesion may not lift due to
tethering by the biliary and pancreatic ducts; (2) The dome effect created by
submucosal injection may cause difficulty in the placement of the snare for effective
en bloc resection[13,70-72]; and (3) increased risk of postresection pancreatitis has been
reported. Currently, the evidence to support submucosal injection before
ampullectomy is not significant. A possible indication may be adenomas with lateral
extraampullary spread[72].

Endoscopic resection
There is no specific type of snare for endoscopic ampullectomy. For the majority of
usual adenomas both hexagonal or oval snares of 3 cm are recommended. Standard
braided polypectomy snares are typically used. The use of a thin wire snare is
advised by some authors, limiting dispersion of the energy and risk of injury to the
pancreatic orifice[72]. Occasionally, a peripheral circumferential incision to the
adenoma with a needle knife device may make easier the snare capture[6]. To resect
the lesion, the tip of the snare is placed on the top of adenoma; then, the snare is
closed maximally and, after previously checking for papilla mobility, the lesion is
sectioned by continuous application of current.

Optimal current
There is no general recommendation regarding the optimal current and power
output for endoscopic ampulectomy. Some investigators recommend pure-cutting
current for this purpose[4,15,73] to preclude the edema originated by the coagulation
mode, although, a pure cutting current has been related to bleeding. Others, using a
blended electrosurgical current[4,6,9] or alternating cut/coagulation modes[6,62,74].
Power output oscillates between 30 W and 150 W[6,9,13,73,75]. Most experts, advocate a
blended current[76]. We prefer to use Erbe electrosurgical generators (Endocut, effect
2)[77].
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Retrieval of resected specimen
Retrieval of the specimen is essential for total evaluation and detection of small
malignant foci. An anti-peristaltic agent administration (e.g., glucagon or hyoscine
butylbromide) to avoid intestinal migration is recommended. Retrieval should be
performed immediately after excision since there is a tendency for the excised
specimen to migrate distally into the jejunum. For this purpose, the snare that was
used for the excision or a retrieval net is ideal. Endoscopic suction can also prevent
the tissue migration. However, the specimen should not be aspirated through the
accessory channel of the duodenoscope into a trap because this could lead to
fragmentation of the specimen. Once retrieved, the specimen can be pinned to a
polystyrene block to aid orientation and facilitate margin analysis.

Residual tissue ablation

After specimen retrieval, the duodenoscope is reintroduced to examine the resection
site for: (1) active bleeding or bleeding stigmata; and (2) residual tissue ablation.
Usually, ablation therapy is used as adjunctive therapy to treat residual
adenomatous tissue remaining after, en bloc or piecemeal, snare resection. With
piecemeal excision, the tissue near the duct holes may be hard to excise completely.
However, the benefits of this adjunctive therapy remain controversial. The overall
success rate was comparable in patients with and without adjuvant thermal ablation
(81% vs 78%, respectively)[9]. Ablation can be performed with monopolar or bipolar
coagulation[49,70], and others devices[11,13,70,78]. We often use argon plasma coagulation
(APC) (setting of 40 to 50 watts) to ablate residual tissue. We carry out a biliary
sphincterotomy prior to fulguration, and we place a pancreatic stent before thermally
coagulating around the pancreatic orifice.

Sphincterotomy and stent placement

The aim with a pancreatic or biliar sphincterotomy and stent placement is to enhance
the technical success and decrease the complications of endoscopic
ampullectomy[4,13,70,79-81]. However, a preresection sphincterotomy has some
drawbacks. First, en bloc resection can be more difficult and will hinder total
9 / 26
histologic evaluation of the resected specimen as result of thermal injury. Secondly, it
may increase risks of bleeding, perforation and tumor seeding[82].
Usually, a meticulous inspection of the ampullectomy site allows identification of
focal biliary and pancreatic orifices within the duodenal wall. Otherwise, secretin
administration can produce juice flow to identify the pancreatic orifice. A 5 French
pancreatic stent placement is advised to decrease the incidence and severity of
pancreatitis[6,9,81,83,84]. Therefore, pancreatic duct stenting after endoscopic
ampullectomy appears recomendable[74]. If ERCP or prior MRCP have demonstrated
a pancreas divisum, pancreatic duct stenting is usually not necessary. Acute
cholangitis after papillectomy is uncommon[76], and prophylactic biliary stent
placement is generally unnecessary. However, we often perform either a biliary
sphincterotomy or a prophylactic biliary stent is placed to minimize this probability.
Biliary stenting may ensure the correct bile drainage if major bleeding occurs. The
pancreatic and biliary stents are generally removed two or three weeks later, at
which time any suspicious-appearing residual polypoid tissue can be removed to
ensure complete excision.

COMPLICATIONS OF AMPULLECTOMY
Complications after endoscopic ampullectomy include bleeding (0%-25%),
pancreatitis (0%-25%), perforation (0%-4%), papillary stenosis (0%-8%) and
cholangitis (0%-2%)[4,6,9,11,13,62,85-87]. Pancreatitis, perforation and delayed bleeding are
the most severe complications[62]. The overall complication rate is around
15%[4,11,49,70,80]. Ampullectomy-related mortality is exceptional, occurring in 0.3%[76].

Bleeding
The duodenal wall has a high vascularization. Bleeding can habitually stopped by
hemostatic procedures (e.g., adrenaline injection, APC, clipping)[88]. If substantial
bleeding is expected then, biliary stent placement is useful to avoid cholagitis. If
massive bleeding occurs, urgent arteriography is probably the best diagnostic and
treatment option. In patients with a high risk of cardiovascular incidents aspirin may
be continued; however, anti-coagulants agents should be discontinued.
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Perforation
Perforation is usually retroperitoneal. Therefore, if perforation is suspected
(endoscopic features, ongoing pain) a computed tomography is more sensitive than
simple radiology. Not all cases of perforation need surgical treatment, selected
patients can be treated conservatively (intravenous antibiotics, gut rest)[6,14]. In
anycase, a multi-disciplinary management is imperative to reach the best result.

ENDOSCOPIC OUTCOMES
The success rates for endoscopic resection of ampullary adenomas is high (range:
45%-92%), with recurrence rates of 0%-33%[9,89]. Intraductal adenoma growth had less
favorable outcomes compared with adenomas without intraductal growth[15].
Predictors of success include: (1) lack of a genetic predisposition to adenoma
formation (e.g., FAP); (2) age > 48 years; (3) male sex; and (4) lesion size < 2.4 cm[70].

ENDOSCOPIC FOLLOW UP AND SURVEILLANCE

After ampullectomy patients should remain fasting for 4-12 h. Then, they are
discharged home on a liquid diet and later continue with a normal diet. To reduce
the risk of ductal lesion, the pancreatic stent should be removed in 2 wk.
Adenoma recurrence can occur in up to 25% of cases despite of complete removal
during the index procedure[6,9,76]. In the absence of symptoms, surveillance
endoscopy can be accomplished using a side-viewing duodendoscope without ERCP.
Intervals change based on the histology and margin status of the resected lesion,
history of FAP, patient age and comorbidities.
Recommended intervals (Table 1): (1) If there was no residual polyp after the
primary resection: endoscopy 3 mo later; (2) If the result is negative for residual
adenoma: surveillance 1 year later; (3) Beyond this, the yield of long-term
surveillance in sporadic ampullary adenomas is unknown. We usually perform
surveillance every 3-5 years; and (4) Given the risk for metachronous duodenal
lesions, patients with FAP should undergo routine surveillance every 3 years.

CONCLUSION
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Advances in endoscopy, EUS and ERCP have influenced the management to patients
with ampullary lesions. Endoscopic ampullectomy has replaced surgical
interventions for the treatment of ampullary adenomas without ductal extension.
Endoscopic ampullectomy has lower morbidity and mortality rates than surgical
approaches. Disadvantages include: difficult technique, few experienced
endoscopists, several procedures to achieve total resection, moderate recurrence rates
(30%), and, as with surgical ampullectomy, the need for postprocedure endoscopic
surveillance. The best technique for endoscopic ampullectomy is subject to the
adenoma size. En bloc resection is recomended for lesions confined to the papilla.
Endoscopic ampullectomy is an effective and safe treatment for ampullary adenomas
in experienced endoscopist but, the endoscopist must be alert to potential
complications. Long-term follow-up information is required to clarify the appropiate
surveillance interval for patients with sporadic ampullary adenomas.

ACKNOWLEDGEMENTS

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Footnotes
Conflict-of-interest statement: Authors declare no conflict of interests for this article.

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Figure Legends

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Figure 1 Technique of en-bloc ampullectomy. A: Lesion is identified; B: Submucosal
(saline + epinephrine) injection; C: With the snare tip anchored above the papillary
mound the entire papilla is snared; D: Check mobility and ensure the snare is firmly
closed; E: En-bloc ampullary resection. Biliary and pancreatic (guidewire) orifice is
identified; F: Biliary and pancreatic stents are placed. Adjuvant APC therapy is
applied; G: Tissue retrieval with the snare; H: Ampullectomy specimen; I: Ampullary
adenoma: tubulovillous architecture that shows neoplastic epithelial cells with
pseudostratified and enlarged hyperchromatic nuclei. Adjacent there is normal
duodenal mucosa. (HE, 20 ×). (Courtesy of Mercedes Hernando, MD). APC: Argon
plasma coagulation.

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Table 1 Recommended intervals for endoscopic surveillance after ampullectomy
Surveillance
No residual polyp after the primary 3 mo later
resection
If negative result for residual 1 yr later
adenoma
Beyond this every 3-5 yr
Patients with FAP every 3 yr
FAP: Familial adenomatous polyposis.

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