29 Ampullary Neoplasia

1. BACKGROUND

The optimal approach has yet to emerge for the manage- ment of sporadic periampullary adenomas and upper gastroin- testinal (GI) neoplasia complicating familial adenomatous polyposis (FAP). There are no randomized trials comparing different surgical and/or endoscopic modalities. Such studies may not be feasible given the infrequency of these conditions and the long follow-up period required for such a study. In the meantime, selection of the optimal approach for an individual patient will rely on a careful evaluation of the disease severity and extent in that patient and the utilization of the best avail- able endoscopic and surgical expertise.

2. INTRODUCTION

The ampulla of Vater is the most common site of neoplasia of the small intestine, related in part to the trophic effects of bile on the mucosa (1–4). This proliferation results in adenomatous transformation and, eventually in some cases, adenocarcinoma.

Ampullary adenomas occur sporadically, but are particularly prevalent in FAP patients, occurring in 50–100% FAP subjects.

Following proctocolectomy, the periampullary area is the most common site of malignancy in FAP subjects. The critical posi- tion of the ampulla and the lag time from adenoma to carcinoma makes this a potential site for surveillance and removal of sig- nificant ampullary adenomas. Endoscopic techniques play a central role in the management of these lesions. However, the optimal approach has yet to be determined.

Endoscopic approaches include surveillance, piecemeal resection, snare ampullectomy, and thermal ablation. Surgical

From: Endoscopic Oncology: Gastrointestinal Endoscopy and Cancer Management. Edited by: D. O. Faigel and M. L. Kochman © Humana Press, Totowa, NJ

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options for advanced lesions include local transduodenal resec- tion, pancreaticoduodenectomy, and pancreas-sparing duo- denectomy. The appropriate management for each patient depends on many factors including the size of the lesion, degree of dysplasia, involvement of the pancreaticobiliary sys- tem, comorbidity, and local expertise.

3. PATHOLOGY

The vast majority of ampullary lesions are tubular or tubulovillous adenomas which arise from the intestinal-type epithelium of the ampulla (5). Foci of severe dysplasia or frank malignancy may be found within a lesion (6). Other forms of ampullary neoplasia are far less common. These include benign lesions (leiomyoma, lipoma, lymphangioma, heman- gioma, and carcinoid) as well as malignancies, both primary and metastatic (lymphoma, melanoma, and metastatic small cell carcinoma) (7).

4. PATHOGENESIS

Regarding FAP syndrome, all nucleated cells in FAP patients

contain one normal and one abnormal adenomatous polyposis

coli (APC) gene (a germline mutation). In the colon, a somatic

mutation in the previously normal (wild-type) APC allele is gen-

erally an early event in carcinogenesis. Accumulation of other

somatic mutations (in genes such as p53 and K-ras) drives the

progression toward malignancy (8). The situation with respect

to periampullary malignancy appears to be similar except that

somatic APC mutations may be relatively less frequent and

K-ras mutations relatively more frequent (9). Another study has

demonstrated p53 mutations associated with high-grade malig-

nant change in periampullary tumors (10). A recent article has

suggested that other familial factors, possibly unidentified modi-

fier genes, may influence the development of periampullary

In a situation analogous to that in the colon, these lesions appear to follow the adenoma–carcinoma sequence. In one study, adenomatous tissue was adjacent to or a component of 84% of periampullary cancers studied (16). A retrospective study by Bleau supported the temporal progression of periampullary ade- nomas to carcinoma, with mean diagnosis of adenoma at age 39, high-grade dysplasia at age 47, and malignancy at age 54 (17).

4.1. FAP SYNDROME

FAP is an autosomal-dominant condition with virtually complete penetration, affecting about 1 in 8000 in the United States (18). Mutation of the APC gene on the long arm of

Fig. 1. Fundic cystic gland polyps. A common phenomenon seen in the proximal stomach of patients with FAP.

Fig. 2. Multiple tiny adenomata in the proximal duodenum (“military”

appearance). Virtually pathognomonic of FAP syndrome.

Fig. 3. Large, nonampullary duodenal adenoma.

adenomas in FAP kindreds explaining, at least in part, the famil- ial segregation of periampullary disease observed in some FAP families (11). This segregation was independent of the kindred’s specific APC mutation. Spigelman and co-workers have reported a correlation between severity of duodenal polyposis and rectal polyposis following colectomy and ileorectal anastomosis (12).

They have suggested that other factor(s), possibly environmental, may be synergistic in some patients, resulting in more severe polyposis at both sites. The authors of this study caution, how- ever, that paucity of rectal polyps does not obviate the need for ampullary surveillance.

The periampullary region is the site of the vast majority of

significant small intestinal adenomas in both sporadic and FAP

patients. These lesions seem to parallel mucosal exposure to

bile, particularly concerning the characteristic inferior exten-

sion of early adenomas (“goatee” appearance). Bile has been

shown to have proliferative (1–3) and mutagenic (4) effects of

gut mucosa. Furthermore, the bile from patients with FAP has

been shown to form more DNA adducts both in vitro and in

vivo than bile from controls (2,13), particularly at low pH (as

found in the proximal duodenum) (14). These DNA adducts

have the potential to give rise to mutagenesis (15).

families. At one extreme is Gardner’s syndrome characterized by GI adenomatous polyps together with other benign neo- plasms such as desmoid tumors, osteomas, and fibromas (22).

Gardner’s syndrome also results from germline APC mutations and is best regarded as part of the spectrum of FAP. Turcot’s syndrome is characterized by central nervous system tumors, often glioblastomas or medulloblastomas (22), together with colonic polyposis. The inheritance of this disorder has been dif- ficult to determine (22), because the association of central nerv- ous system tumors and polyposis might arise through germline mutation of more than one gene (23). Germline APC mutations have been identified in some subjects with Turcot’s syndrome, particularly those with cerebellar medulloblastomas and pro- fuse colonic polyposis (23). For the purposes of this chapter, the term FAP incorporates Gardner’s syndrome and those cases of Turcot’s syndrome attributable to APC mutations.

The duodenum is the commonest site of malignancy in FAP patients following colectomy, occurring in 4.5–8.5% (24,25).

Adenomas and carcinomas have also been encountered in the distal ileal segment and within ileoanal pouches 5–10 yr after proctocolectomy (26).

5. INCIDENCE

An understanding of the natural history of duodenal neo- plasia in FAP patients is essential to the development of sur- veillance strategies and decisions regarding management in this condition. Periampullary tumors represent 5% of GI tumors and 36% of resectable pancreaticoduodenal tumors (10). The periampullary adenoma is an uncommon lesion in clinical practice, although not as rare as previously thought.

An early review by Baggenstoss demonstrated 25 of these lesions in 4000 consecutive autopsies (0.62%), suggesting that the lesion may be subclinical (27). A review of the case notes in this study suggested that perhaps six of these lesions (24%) might have been symptomatic.

Asymptomatic adenomatous change of the ampulla is very common in FAP patients, occurring in up to 100% of subjects (17). The incidence of FAP-related duodenal and peri- ampullary adenomas depends on the diligence of surveillance.

A review of the Johns Hopkins FAP registry indicated that the relative risk of duodenal adenocarcinoma in FAP compared with the general population was 330 and the relative risk of

ampullary cancer was 123 (28). The combined absolute risk of duodenal cancer in FAP patients was, however, only 1/1698 years. Because follow-up was incomplete and most cancers occur later in life, this risk of malignancy may be an under- estimate. A study from the United Kingdom reported develop- ment of malignancy in 3 of 70 patients followed over 40 mo (29). It is important to remember, therefore, that although adeno- matous change in the duodenum may be almost universal in FAP only a small percentage of patients develop cancer.

Several studies have indicated that the median age at onset of periampullary malignancy complicating FAP is in the sixth decade (11,25,28).

6. CLINICAL PRESENTATION

Lesions of the periampullary area may be asymptomatic but can also present relatively early with symptoms of pancreatico- biliary origin. Clinical presentation is usually a consequence of obstruction, resulting in abdominal pain, cholangitis or jaundice (7) or, less commonly, recurrent pancreatitis (30).

Courvoisier’s sign is occasionally present, suggesting advanced disease (31). Biochemical evidence of biliary obstruction is common in symptomatic patients (32). The diagnosis is usually unsuspected prior to visualization of the ampulla, with most patients thought to have pancreatic malignancy or choledo- cholithiasis.

7. ENDOSCOPIC MANAGEMENT OF PERIAMPULLARY ADENOMA

7.1. DIAGNOSIS

In patients with FAP, diagnosis of upper GI and particularly periampullary adenomas depends on the vigilance of the endo- scopist. Examination with a side viewing duodenoscope is essential. Two recent studies have demonstrated that duo- denoscopy with a forward-viewing endoscopy missed 50% of

Fig. 5. Moderate-sized ampullary adenoma.

Fig. 6. Steps in snare ampullectomy: (A) ampullary adenoma; (B) appearance after snare removal using blended current; (C) pancreatic orifice accessed with a hydrophilic wire; (D) temporary (<1 wk) pancreatic stent placed following pancreatic sphincterotomy; (E) final result 3 mo later.

(Color versions of A and E appear in the color insert following p. 84).

gross lesions visible with the side-viewer (17,33). Careful biopsies of the ampulla may detect early adenomatous change in light of the somewhat “frond-like” appearance of many nor- mal papillae. In one study six of eight normal-appearing ampullae demonstrated microscopic adenomatous change at biopsy (17). However, care should be taken to avoid the ampullary os, because even cold biopsies can result in pancre- atitis. Most lesions demonstrate adenomatous-appearing pro- liferative tissues, but occasionally a mass will arise within the ampulla and present as a bulging ampulla covered with normal mucosa. Sphincterotomy to access the tissue is necessary in this situation. The differential diagnosis of a bulging ampulla includes choledocholithiasis, type III choledochal cyst, and perhaps duodenal wind-sock diverticulum (although this is not an ampullary lesion).

As a result of the poor sensitivity of endoscopic biopsies regarding malignant change, endoscopic retrograde cholan- giography is an essential part of the management of a patient with an adenoma involving the ampulla. Sphincterotomy per- mits sampling of the intra-ampullary mucosa whereas exten- sion along the pancreaticobiliary system will be revealed by cholangiopancreatography, a situation rendering the patient unsuitable for definitive endoscopic therapy.

Because management decisions will hinge on endoscopic biopsies, it is important to appreciate the limitations of endo- scopic biopsy as an indication of dysplasia. Surface biopsies may underestimate the degree of dysplasia within the lesion.

In one study, endoscopic biopsy failed to identify infiltrating malignancy in 7 of 23 cases (32%) (34). The accuracy of endo- scopic biopsy was increased following biliary sphincterotomy and access to “deeper” tissue.

this area reliably owing to compression of the affected tissues.

This difficulty is may be prevented by infusing water into the duodenum. In spite of this, EUS can afford excellent views of the region including the duct systems. Recent studies have indicated that EUS is useful in the tumor-node-metastasis stag- ing of periampullary malignancy, with staging accuracy as high as 84% (34–38). In a recent study the T-stage accuracy was 82% and nodal accuracy was 71% (39). In another study, however, the diagnostic accuracy of EUS was only 44% in 23 patients with periampullary lesions (34). Intraductal ultrasound may provide useful information regarding intraductal exten- sion. This approach requires further evaluation.

7.2. SURVEILLANCE

As early as 1950, Halsted advocated upper GI surveillance of FAP subjects (40). Given the risk of progression to malig- nancy, concerns regarding residual adenomatous tissue after ablation or resection and the ongoing proliferative nature of these lesions, surveillance appears justified, although no stud- ies have demonstrated improved survival as a result. An ideal regimen for surveillance of these lesions has yet to be deter- mined. As discussed earlier, virtually all patients with FAP will eventually have at least microscopic involvement of the ampulla and most will have multiple tiny adenomata spread over the proximal duodenum. It is impossible to remove all adenomatous tissue in FAP patients and the aim of surveil- lance in FAP patients is to sample tissue in order to detect advancement to high-grade dysplasia. Large lesions are more likely to contain foci of high-grade dysplasia or malignancy.

Therefore it is our practice to remove or ablate lesions larger than 5 mm and grossly polypoid papillae. Sporadic adenomas, on the other hand, occur as isolated lesions, and the aim of surveillance is to detect recurrence at a previous site of therapy (either endoscopic or surgical).

The optimal time interval for surveillance in FAP patients remains to be determined. Two authors have suggested surveil- lance every 3–5 yr (41,42) Spigelman and co-workers have (retrospectively) developed a scoring system to determine which patients are most likely to progress to malignancy and therefore warrant more intense surveillance (see

It is important to consider that patients with FAP may have adenomas beyond the ampulla and not seen with standard endoscopy. Therefore, an appropriate surveillance strategy in

separation of pancreatic and biliary orifices. Most authors would advocate completion sphincterotomies to reduce the risk of sub- sequent orifice stenosis.

FAP patients might include extended duodenoscopy with either a colonoscope or push enteroscope.

7.3. THERAPY

The ideal endoscopic therapy for periampullary adenomas has not been established. Excision has the advantage of submitting ample tissue for histological examination. In practice, endoscopic therapy for these lesions usually involves excision of the bulk of the lesion followed by tissue ablation of residual adenoma at the conclusion of the initial endoscopic session and at follow-up examinations. Shemesh and co-workers (44) published their early experience with sphincterotomy and fulguration of adenomatous periampullary tissue in 1989. Four patients with recurrent disease

after local surgical resection were treated with fulguration. None had evidence of recurrence with a 12- to 24-mo follow-up.

The first step in endoscopic removal of the ampulla com- prises assessment of intraductal extension of the adenoma. Any lesion extending beyond the wall of the duodenum is clearly beyond definitive endoscopic treatment. This is most easily determined by cholangiopancreatography or possibly EUS.

Endoscopic removal of the ampulla may be performed either in a single piece (snare ampullectomy), or using a piece- meal resection technique.

7.3.1. Snare Excision

This technique comprises removal of the tumor using a small snare in one piece. The procedure may be preceded by sub- mucosal saline injection. Advocates of this technique believe that it increased the distance between serosa and the snare, thus making the procedure safer. However, as the ampulla is teth- ered by the ductal complex, it does not rise in quite the same fashion as a colonic polyp and occasionally can become more difficult to effectively snare with a large cushion of saline.

A modification of the snare technique (not widely prac- ticed) is to inflate an occlusion balloon in the distal bile duct and retract the tissue toward the snare in an effort to better snare deep tissue (45). Snare removal of the entire papilla was described in a large cohort by Binmoeller and co-workers in 1993 (46). In a recent report of 28 ampullectomies from the Mayo Clinic immediate complications were minor bleeding (n = 2), mild pancreatitis (n = 4), and a duodenal perforation (n = 1). Papillary stenosis resulting in pancreatitis occurred in two patients (17%) at 4 and 24 mo. Follow-up endoscopy revealed recurrent/residual ampullary adenomatous tissue in two (10%) (47). These recurrence rates following snare ampul- lectomy compare favorably with transduodenal ampullectomy (34). Martin et al. (48) reported 14 consecutive patients treated with snare ampullectomy. One patient died from necrotizing pancreatitis and another required surgery for hemorrhage. The patient who died did not receive a prophylactic pancreatic stent. Recurrence has occurred in 4 out of 10 patients with a mean follow-up of 31 mo. Another study of eight patients (49) reported one episode of cholangitis following snare ampullec- tomy, but no other complications. Two patients had invasive malignancy in the snared specimen and went on to have pan- creaticoduodenectomy. The remaining six patients remain well with no recurrence at mean follow-up of 12 mo.

Clearly a major concern with snare ampullectomy is the potential for acute pancreatitis. This occurs in about 15–20%

of cases (46,47) and can be fatal (48). Identification of the pan- creatic orifice after snare ampullectomy may not be possible.

In the Mayo series, about 50% of patients had a temporary stent placed (at the discretion of the endoscopist) but no differ- ence in pancreatitis rates was reported between those with and without stent insertion. Nonetheless it is possible that stenting the pancreatic duct may modify the severity of subsequent pancreatitis and it appears to be prudent.

7.3.2. Piecemeal Resection

Concerns regarding pancreatitis have led some authors to a piecemeal technique for adenoma resection performed after the insertion of a pancreatic stent. The patient initially undergoes a

ductal extension. (A) Endoscopic ultrasound image. (B)

Endoscopic

retrograde cholangiography

plications such has pancreatitis, transmural burn, and perforation have generally led to the use of less aggressive ablative therapy (17) such as monopolar ablation following sphincterotomy. A fistulatome allows precise targeting of tissue for ablation. Argon plasma coagulation may be an attractive method for destroying residual tissue given its relatively shallow depth of injury.

8. SURGICAL THERAPY

The long-term results of endoscopic resection and ablative therapy are not known, whereas the limitations of endoscopic biopsy in excluding malignancy are well documented, with false-negative results of up to 56% (34). The two surgical options for these lesions are pancreaticoduodenectomy (Whipple procedure) and transduodenal excision.

Gray has reported pancreaticoduodenectomy for five patients with benign adenomas and eight with adenomas containing foci of malignancy (52). Two of the patients with benign lesions died in the peri-operative period, but the three survivors were free of disease at follow-up. Five of eight patients with invasive malig- nancy were also free of disease at follow-up. The cost of Whipple’s procedure is higher potential morbidity and mortality (34,53). Complications and hospital stay following this surgery are significantly longer than with local resection (34).

Transduodenal excision is not a new technique, having been reported for ampullary lesions by Halsted in 1899 (54).

Transduodenal excision has been used as a less invasive surgi- cal alternative to pancreaticoduodenectomy (32,34,53,55,56).

Unfortunately, transduodenal resection may be inadequate therapy in many patients. Recurrence of benign adenomas has been reported in 25–33% (32,34,56). In one study, four of four subjects treated had recurrence of adenoma at 24-mo follow- up (44). In a study of 12 patients, resection margins were inade- quate in 50%, leading to conversion to pancreaticoduodenectomy in 3 patients (34). In contrast to the above results, a more recent study by Posner and coworkers reported 89% total excision rate in 21 patients, 3 of whom had malignancy (57). There was, however, one death.

FAP patients are a particularly difficult treatment group owing to the widespread nature of mucosal involvement. Recurrent duodenal adenomas following transduodenal resection (mean recurrence: 13 mo) has led one group to conclude that this is inadequate therapy for these patients (58). Furthermore, the

(61). After 6 mo of treatment there was a reduction in epithe- lial proliferation in the sulindac group but no significant regression of large polyps. However, blinded review of video- tapes demonstrated significant regression of small polyps (<2 mm) compared with the placebo group. This evidence supports the hypothesis that sulindac might also have an effect on polyp proliferation in the duodenum. However, it remains to be seen whether this will translate into a clinically signifi- cant benefit.

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