Surgical Approaches to Benign and Malignant Tumors of the Ampulla of Vater

POLYPS OF THE GASTROINTESTINAL TRACT

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SURGICAL APPROACHES TO BENIGN AND MALIGNANT TUMORS OF THE AMPULLA OF VATER Jaime A. Rivera, MD, David W. Rattner, MD, Carlos Fernandez-del Castillo, MD, and Andrew L. Warshaw, MD

Ampullary tumors include a diverse group of benign and malignant neoplasms. Surgery was first performed on an ampullary tumor in 1989 by Halstedz4 and has evolved into a spectrum of options designed to relieve symptoms and remove malignant or potentially malignant lesions. The surgical management of ampullary tumors involves decisions that consider various issues, including the nature of the tumor, the coexistent medical illnesses and condition of the patient, and the specific goals of the procedure. In order to make such decisions appropriately, an awareness of the various ampullary tumors, their symptomatology, methods of diagnosis and evaluation, and the specific benefits and potential problems associated with the differing surgical options is necessary. This article discusses these issues with emphasis on both the currently accepted and the controversial aspects of ampullary tumor management. AMPULLARY TUMORS: GENERAL CONSIDERATIONS

In 1720, Abraham Vater described an ampullary structure in the duodenal wall that currently bears his name.lz The ampulla of Vater is an epithelial confluence formed by the intraduodenal bile duct, terminal pancreatic duct, and duodenal mucosa. It is sac-like in nature, is surrounded by the muscular sphincter of Oddi, and empties into the duodenum through a prominence in the duodenal wall, which is termed the papilla of Vater. A true ampulla is present in only one half of the population.12 Its absence results from variations in pancreatic and bile duct anatomy in which no common entrance into the duodenum exists. From the Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 5 . NUMBER 3 . JULY 1996

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Ampullary tumors may be classified as either epithelial or nonepithelial. Epithelial tumors develop directly from the ampulla itself or from any of the epitheNonepithelial tumors probably originate from lial components that form it.12,55 stromal elements or from neuroendocrine cells. Most epithelial tumors involve multiple components of the ampulla at the time of excision.79As a result, the precise site of origin is often difficult to determine both clinically and pathologi~ally.3 ~ ~ difficulty ~~ This has given rise to the term periampullary tumors, which describes the entire group of neoplastic lesions that arise at or near the ampulla. The term periampullary tumors is nonetheless a source of confusion, because it describes a heterogeneous group of tumors and it has been subject to varying interpretations. Some experts maintain that periampullary tumors are limited to tumors that originate from the epithelial structures of the ampulla,5O including intraduodenal bile duct, terminal pancreatic duct, and adjacent duodenal mucosal tumors, as well as the common ampullary channel tumors. Others contend that the term also includes pancreatic head tumors.29However, including pancreatic head tumors within the periampullary tumor group is problematic. Cancer of the pancreas has a much worse prognosis than cancer of the amThis difference underscores the pulla, distal bile duct, or importance of distinguishing pancreatic cancer from other periampullary cancers. In addition, ampullary, duodenal, and distal bile duct tumors are respectively associated with different clinical outcomes. Several investigators have found higher long-term survival rates for patients with ampullary cancer compared with patients with duodenal and distal bile duct ~ a n c e r . Although ~ , ~ , ~ ~ the basis of these prognostic differences is not well understood, it may reflect differences in symptom onset and in stages of disease at the time of diagnosis. Alternatively, it may be related to intrinsic biologic differences among the various tumors. Whatever may account for these differences, it is clear that periampullary tumors comprise a diverse group of neoplasms. This discussion focuses on true ampullary tumors and distinguishes them from other periampullary tumors whenever possible. AMPULLARY TUMORS: PREVALENCE AND PATHOLOGIC CONDITION Benign Tumors

Benign tumors of the ampulla are relatively uncommon and include lipomas, leiomyofibromas, hemangiomas, neurogenic tumors, and adenomas (Table 1).6,65 The most common benign tumor of the ampulla is the a d e n ~ m aPrior . ~ ~ to 1980, fewer than 100 benign ampullary tumors were reported in the literatui-e.34Approximately 70 of these tumors were associated with symptoms.65Our review of the English literature since 1980 identified 56 additional benign ampullary tumors, all of which were adenomas.4,6,8,16,27,29,33,34,39,55,56,79,80 Reports of benign ampullary tumors may continue to increase with more frequent use of upper gastrointestinal (GI) endoscopy. In support of this, a single review of duodenal endoscopic biopsies performed between 1982 and 1990 reported 19 benign tumors in 125 patients.33Additionally, Rattner and Warshaw et al.48recently reviewed 28 ampullary tumors resected at the MassachusettsGeneral Hospital between 1988 and 1995 and found four patients with tumors identified during endoscopic evaluation of dyspepsia. Adenomas

Calzavara was the first to describe an adenoma of the ampulla in 1895.59 Recent postmortem studies suggest that ampullary adenomas occur at a frequency

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Table 1. AMPULLARY TUMORS Benign lipoma leiomyofibroma hemangioma neuroma hyperplastic polyps inflammatory polyps Potentially Malignant adenomas (tubular,tubulovillous,and villous) some neuorendocrine tumors (somatostatin, gastrin, insulin, and pancreatic polypeptideproducing carcinoids) Malignant adenocarcinoma adenosquamous carcinoma leiomyosarcoma fibrosarcoma non-small cell neuroendocrine carcinoma small cell neuroendocrine carcinoma

of 0.04% to 0.12% and usually arise between the fifth and seventh decades of life.59 others Whereas some investigators have found a higher incidence in have failed to find a sex predilection.65 Ampullary adenomas may be sessile or pedunculated and may contain tubular, tubulovillous, or villous histologic feat u r e ~ . ~There ~ , ~may ~ , ~ be~a ,progression from tubular to tubulovillous to villous .~ ~ adenoma~.~~ An adenoma-carcinoma sequence similar to that present in colon cancer has been postulated for ampullary adenomas and is supported by the frequent finding of invasive cancer within adenomas as well as the common adenomatous charSeifert et a159 acteristics observed at the borders of ampullary cancer ~pecirnens.~~ found that 30% of ampullary adenomas studied contained carcinoma and that 41% of ampullary carcinomas contained residual adenomatous tissue. Other investigators report a frequency of malignant components in 30% to 40% of adenomas and the presence of adenomatous elements in 30% to 91% of ampullary cancer specimens.55 -

Villous Adenomas

The risk of malignant transformation appears to be greater in villous adenomas than in tubular a d e n ~ m a s . ~Perzin ~ , ~ ' and Bridge47found invasive cancer in 60% of villous adenomas but in only 22% of tubular adenomas. The prevalence of malignant change also increases with an increase in size of the a d e n ~ m aLarge .~~ villous adenomas appear to have the same degree of malignant potential as their colonic counterpart^.^^ Ampullary adenomas also are associated more frequently with carcinoma than are adenomas in other parts of the duodenum.59Interestingly, duodenal villous adenomas seem to have a predilection for the ampulla. Ryan et a153found that 16 of 19 duodenal villous adenomas studied were located at the ampulla. They reasoned that this association might be explained by the possible presence of carcinogens or cocarcinogens in biliary or pancreatic secretion^.^^ Villous adenomas of the ampulla become clinically evident by virtue of their anatomic location. Small villous adenomas may be asymptomatic, but larger ones (Fig. 1) may obstruct the biliary and pancreatic ducts and cause abdominal pain,

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Figure 1. lntraoperative view of a large ampullary villous adenoma. Sutures retract the duodenal edges exposing the friable villous tumor.

jaundice, or acute p a n c r e a t i t i ~ . ~Fifteen ~ , ~ ~ .percent ~~ of patients presented with acute pancreatitis in Ryan et review of duodenal villous adenomas. Villous adenomas may extend 1to 2 cm up the ductal system. Reportedly, more than 75% of patients with ampullary villous adenomas are icteric, and occult or gross GI bleeding is also common due to the friability of villous turn or^.^^,^^ Villous adenomas also may cause duodenal obstruction, intussusception, or dyspepsia.53 Coexistent biliary tract stones are present in up to 30% of villous a d e n o m a ~ . ~ ~ Although this association is not well understood, it might be attributed to the incidental discovery of villous adenomas during the evaluation of primary biliary disease. It is possible that ampullary neoplasms could retard the passage of stones through the ampulla that might otherwise have passed, thereby increasing the odds of finding such a combination. A similar association between cholelithiasis or choledocholithiasis has also been observed for ampullary cancer.25

Ampullary Adenomas and Familial Polyposis

Adenomas of the ampulla may arise sporadically or in association with polyposis syndromes. These syndromes are rare and account for a small minority of GI cancers. However, the presence of such a syndrome in patients with ampullary adenomas affects their surgical management and therefore warrants discussion. The most common of these syndromes and best characterized is familial adenomatous polyposis (FAP).52 FAP is an autosomal dominant inherited disorder characterized by the deThe disorder velopment of multiple adenomatous polyps that arise in the is associated with an inherited defect in the adenomatous polyposis coli (APC) gene, which normally suppresses tumor growth. Patients with FAP inherit defective APC genes from one parent and therefore develop colon cancer at a greater frequency than the general population, possibly because they only require subsequent defects in the remaining APC gene. This explains the high rate of pro-

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gression of adenomatous polyps to cancer in patients with FAP. One hundred percent of patients with FAP develop colon cancer by the fourth decade of life if Therefore, all patients with FAP should undergo prophylactic left ~ntreated.~B colectomy as young adults. Adenomatous polyps in patients with FAP also can be found in the upper GI tract.z8The duodenum and ampulla are the most common sites of extracolonic adenomas and carcinomas in patients with FAP.28Like sporadic adenomas, ampullary and duodenal adenomas arising in patients with FAP are premalignant. However, the risk of malignant change in ampullary adenomas associated with FAP is greater than in sporadic adenomas. The relative risk of developing ampullary adenocarcinoma in patients with FAP is more than 120 times greater than that of the general p o p ~ l a t i o n . ~ ~ The greater risk of periampullary cancer development in patients with FAP suggests that a more aggressive surgical approach is warranted. The potential to develop cancer in the residual duodenum that remains after tumor excision must be considered in addition to the relative risk of cancer in the excised adenoma. Although there are no fixed guidelines for the frequency of upper GI endoscopic surveillance in patients with FAP, institutions that contain polyposis registries recommend endoscopy every 1to 2 years, with removal of large suspicious polyps whenever possible. Neuroendocrine Tumors

Emory et all4categorize ampullary neuroendocrine tumors within a histologic spectrum of increasing malignancy from low-grade carcinoid tumors to intermediate non-small cell carcinoma to high-grade small cell cancers. Carcinoid tumors are the most common primary neuroendocrine tumor of the ampulla (Fig. 2).14As of 1994, 42 primary ampullary carcinoid tumors, five small cell carcinomas, and one non-small cell carcinoma were reported in the world literature.I4

Figure 2. In contrast to villous adenoma, this intraoperative view of an ampullary carcinoid tumor shows a submucosal mass arising at, but not obscuring the ampulla. The ampullary orifice has been cannulated with a 5-Fr catheter.

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Approximately 33% of ampullary carcinoid tumors are found in association Conversely, most periamwith von Recklinghausen's neurofibromatosis (NF).49,69 pullary carcinoid tumors associated with NF arise at the ampulla (54%),whereas 38% develop from the duodenum, 5% from the pancreas, and 3% from the bile ducts.49This predilection for the ampulla may result from the transformation of an endodermal-ectodermal complex located near the ampulla.49

Figure 3. Microscopic view of ampullary carcinoid tumor producing somatostatin. A, Lowpower view demonstrates cells forming pseudorosettes around small capillaries.B, Laminated psammoma body within the tumor. C, lmmunohistochemical staining shows intracellular somatostatin (arrows). (From Erbe RW, Compton CC: MGH case records. N Engl J Med 320:996, 1989; with permission. Massachusetts Medical Society. All rights reserved.)

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Histologically, carcinoid tumors are composed of a uniform cell population with central round nuclei, a granular cytoplasm, and rare or no mitotic figures.'4.15 The cells may be arranged in compact nests, rosettes, ribbons, or trabeculae or in a diffuse solid pattern.14Mineralized concretions termed psammoma bodies are commonly found in somatostatin-rich duodenal carcinoid tumors (Fig. 3 ) . l 5 In fact, most duodenal and ampullary carcinoid tumors associated with NF are somatostatin-rich tumors, termed somato~tatinomas.~~,~~ However, duodenal carcinoids are nonfunctioning tumors and are not known to cause the systemic somatostatinoma or carcinoid syndrome^.'^,'^ Staining of ampullary neuroendocrine tumors also has demonstrated insulin, gastrin, and pancreatic polypeptide hormone production.15 Patients with NF and abdominal pain should be evaluated for ampullary carcinoid tumors, because 10% to 15% of periampullary neurofibromas eventually show malignant change.69Endoscopic biopsies may be diagn0stic,6~but they occasionally fail due to the submucosal nature of carcinoid tumors. Lymph node metastases have been reported in up to 53%of ampullary carcinoid tumors smaller fact that must be considered when determining the surgical manthan 2 ~ m , a4 ~ agement of ampullary carcinoid tumors. Non-small cell and small cell neuroendocrine carcinomas appear to behave like their malignant counterparts in the lung and may have a worse prognosis than ampullary carcinoid tumors.13Emory et all4reported the first non-small cell ampullary neuroendocrine tumor in 1994 and noted that it contained histologic features characteristic of carcinoma. The cells are atypical, with hyperchromatic nuclei and markedly increased numbers of mitoses compared with carcinoid tumors. Emory et all4 noted that ampullary small cell neuroendocrine tumors also have malignant features and appear to be more aggressive. Four of the five reported patients with ampullary small cell carcinomas died within 17 months of surgery despite the use of radical resection in three.I4

C; Figure 3 (Continued)

Stromal Tumors

Sarcomas may arise at the ampullaz9and include leiomyosarcomas and fibrosarcomas. They may be polypoid or ulcerating ampullary lesions58and are often submucosal. A high frequency of mitotic figures (>5 per high power field or >5 per 100 cells) at histologic evaluation differentiates leiomyosarcomas from their benign counterpart^.^^ However, endoscopic biopsy frequently fails to allow adequate differentiation between benign and malignant lesions. In fact, the diagnosis of low-grade malignant leiomyosarcomas may require the demonstration of metastases because surgical specimens also may fail to demonstrate unequivocal indices of m a l i g n a n ~ y . ~ ~ Ampullary Carcinoma

Ampullary adenocarcinoma accounts for 10% to 36% of all surgically resectable pancreatoduodenal malignancies and may be the most curable of all upper digestive tract carcinoma^.^^,^^ It represents 0.2% of GI tract malignancies found at Although reports of a sex predilection have varied, our review of the English literature suggests a male predominance (Table 2). Adenocarcinoma of the ampulla usually becomes clinically evident between the ages of 55 and 65.71 The current TNM staging system for ampullary cancer is shown in Table 3, and a typical ampullary carcinoma is presented in Figure 4. Adenosquamous carcinomas have been identified at the ampulla but are quite rare.(j7 Multiple factors influencing the survival of patients with ampullary cancer have been evaluated, the results of which have been variable. Those results reported since 1975 are listed in Table 2. The variability among these reports precludes any definite conclusions regarding prognostic factors. As is expected, however, lymph node metastases, tumor grade, and stage appear to be the most influential factors. AMPULLARY TUMORS: CLINICAL EVALUATION Signs and Symptoms

The clinical presentation and evaluation of benign ampullary tumors overlaps that of malignant tumors. Signs and symptoms associated with ampullary tumors develop secondary to their anatomic location. Specifically, such tumors may obstruct the biliary and pancreatic ducts, resulting in jaundice, abdominal pain, acute ~ , ~friability ~ , ~ ~ , ~ of ~ ampullary tumors also cholangitis, or acute p a n ~ r e a t i t i s ? ' , ~The may induce acute or chronic GI bleeding.53Ampullary cancer "classically" presents with a triad of fluctuating painless jaundice, a palpable gallbladder, and anemiaZ4;however, this triad was not present in patients reviewed at our i n s t i t ~ t i o n ~ ~ or in most reports that we reviewed and therefore should not be considered classic. Jaundice is the most common presenting symptom associated with ampullary tumors. Sixty-three percent of patients with ampullary tumors evaluated by Ryan et a153at the Massachusetts General Hospital were icteric at presentation. Interestingly, jaundice occurred in 83% of these patients with malignant ampullary tumors but in only 29% of the patients with benign tumors.53The average incidence of jaundice was 75% in other ampullary cancer reports published since 1975. Jaundice may be persistent or fluctuating and may occur with or without abdominal pain.25Some investigators have suggested that fluctuating jaundice correlates with a better prognosis than does persistent jaundice, perhaps reflecting tumor size variati01-1.~~

Table 2. RADICAL RESECTION OF AMPULLARY CANCER SINCE 1975

Author

No. of Patients with Mean Age Radical Men:Women of Patients with Operative 5-Year Resection of with Year Ampullary Ampullary Ampullary Mortality Survival Published Period Tumors Cancer Cancer (%) (%)

Warren72 Wise78 Markipo~r~~

1975 1976 1976

42-71 50-68 55-74

112 39 23

Nakased5 Akwaril

1975 1977

49-74 50-72

334 87

TreadweIlfi8 Sch1ippe1-t~~ Forestlg Williams77 Cohen9 HerterZ6 Kellum31

1978 1978 1979 1979 1982 1982 1983 1985 1986 1986 1986 1987 1987

50-65 40-76 56-76 49-71 40-80 40-78 49-82 62-84 76-81 75-84 50-84 49-85 59-83

19 31 21 27 22 44 17 36 24 18 45 31 26

K ~ o x ~ ~ Gracez1 Tarazifi7 Hayesz5 Robert~on~~

-

-

-

-

-

1.2:l -

1.6:l 4.5:l

-

32 62 17

60

16 11

6 34

61 61

16 22.6 14 11 24 15 12 30 13 25 8

32 10 24 27 30 28 50 32 41 62 37 53 34

-

-

-

-

-

3: 1 1:1.7

-

-

-

-

62 59

2.41 1.6:l

11 15 8

65

Negative Prognostic Factors

Evaluated, But Not Significant Prognostic Factors

+ LN + LN

-

+ LN, papillary tumors -

+ LN, papillary, grade

-

abdominal pain, bilirubin level -

stage, gender duration

-

-

-

-

-

-

+ LN

-

-

-

-

-

-

-

-

-

-

grade

stage (continued)

QI

\O

w

Table 2 (Continued).

Author

No. of Patients with Mean Age Radical Men:Women of Patients Resection of with with Operative 5-Year Year Ampullary Ampullary Ampullary Mortality Survival Published Period Tumors Cancer Cancer (%) (%)

Negative Prognostic Factors

Cristl" 1987 N e o p t o l e m o s 4 V 988

69-86 72-84

19 19

1:1.25

66

-

36 52

grade, stage

Michelassi4' Dawson12

1989 1989

46-87 43-85

23 24

1.27:l 1.2:l

60 57

22 -

32 55

sulfated mucin

ShutzeG3 Martin3= M~nson~~

1990 1990 1991

53-88 79-88 65-89

24 23 104

3.0:l 1.3:l

64 64

40 6

61 43 34

+ LN + LN, grade, +margins

Matory40

1993

83-90

55

1 :1

64

3

43

resectability

Wei7= Willett76 SpertiG6 Andersen5 ShyrS4 ShiraiG2 Allema2

1993 1993 1994 1994 1994 1995 1995

62-91 81-90 71-90 76-91 65-92 75-91 84-92

69 41 27 25 100 40 67

1.1:l 1.4:l 4:1 1.1:l 1.7:l

63 63 -

12 3 18 3

52 55 56 34 45 54

-

58 60 61

-

-

-

lymphatic invasion

-

+ LN, + margins stage, grade + LN, stage, grade -

stage +margins, vascular invasion, normal amylase

Evaluated, But Not Significant Prognostic Factors

+ LN tumor size, age, sex -

size, + LN, age, lymphatic invasion -

tumor size grade, LN, tumor origin, jaundice gender, weight loss LN, stage, margins, size

size

size > 2 cm,

+

LN, grade, blood loss, age, gender

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Table 3. TNM CLASSIFICATION OF AMPULLARY CANCER T: Primary Tumor TX Cannot be assessed TO No evidence of primary tumor Tis Carcinoma in situ T I Tumor limited to the ampulla of Vater T2 Tumor invades duodenal wall T3 Tumor invades pancreas (less than 2 cm invasion), adjacent organs, or both T4 Tumor invades pancreas (more than 2 cm invasion), adjacent organs, or both N: Lymph Node Status NX Cannot assess regional lymph nodes NO No regional lymph node metastases N1 Regional lymph node metastases present M: Distant Metastases MX Cannot assess distant metastases MO No distant metastases identified M2 Distant metastases present Stage Grouping Stage 0: Tis, NO, MO Stage I: T I , NO, MO Stage ll: T i -2, NO, MO Stage Ill: TI-3, N1, MO Stage IV: T4, Any N, MO Any T, Any N, M I Adapted from Willett CG, Warshaw AL, Convey K, et al: Patterns of failure after pancreatoduodenectomy for ampullary carcinoma. Surgery Gynecology & Obstetrics 176:33,1993; with permission, now known as the Journal of the American College of Surgeons.

A b d o m i n a l p a i n a n d weight loss were the next most c o m m o n symptoms as~~ of ampullary tumors f o u n d sociated with a m p u l l a r y cancer. R y a n et ~ 1 1 ' sreview abdominal p a i n in 6 of 19 (32%) patients a n d weight loss in 3 o f 19 (16%). Since 1975, the average incidence of weight loss in the setting o f cancer was 53% a n d that of abdominal p a i n was 39%. Some experts have associated abdominal p a i n w i t h a worse prognosis, attributing i t t o perineural invasion.38

Figure 4. Gross pathologic specimen of ampullary adenocarcinoma after radical resection. The tumor obscures and invades the am~ulla.

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Physical signs and laboratory findings associated with ampullary tumors also reflect ductal obstruction or GI bleeding. Scleral or cutaneous icterus is common. Other physical findings include hepatomegaly, a palpable gallbladder, and occult blood in the stool. A palpable gallbladder has been reported in 13% to 65% of patients with ampullary cancer.71This variation may be affected by biliary decompression occurring prior to referral to major centers. Alternatively, it may be related to the various stages of illness in which patients present. Occult GI bleeding in the setting of jaundice should raise the suspicion of an ampullary tumor, although it also may occur in association with gallstones, hemobilia, and acute alcoholic he pa ti ti^.^^ Laboratory Tests

Laboratory studies add little to the diagnosis of ampullary tumors except in giving support to the diagnosis of obstructive jaundice or GI bleeding. Measurement of the serum alkaline phosphatase level is the most sensitive serum indicator of obstructive jaundice. It frequently increases disproportionately to serum bilirubin and transaminase changes. Examination of the stool for gross or occult bleeding also may lend indirect support to the differential diagnosis of ampullary tumors, rather than pancreatic or biliary tumors. Evaluation and Staging

Imaging studies are applied to the evaluation of ampullary tumors for purposes of diagnosis, staging, and determination of resectability. The presence of distant metastases or major vascular invasion associated with ampullary tumors precludes attempts at curative resection. Useful imaging techniques include abdominal ultrasound (US), computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS). Abdominal US and CT are frequently the initial imaging studies. US accurately distinguishes between obstructive and nonobstructive jaundice but is limited in its ability to localize the site or cause of the o b s t r ~ c t i o nAlthough .~~ CT is more sensitive in determining the cause of obstructive jaundice, it too often fails to identify ampullary tumors, which tend to be relatively small and get lost in the adjacent duodenal folds. In a recent study, US and CT were able to delineate This surprisingly ampullary tumors in only 7% and 29% of cases, re~pectively.~~ Most often, low sensitivity rate has been corroborated by other inve~tigators.~~ additional means (particularly endoscopy) must be used to identify ampullary tumors with certainty. However, CT and US remain of particular value for the evaluation of distant metastases, and CT is valuable for the evaluation of portal and mesenteric venous invasion. Studies evaluating the accuracy of CT in assessing ampullary and periampullary tumors must be interpreted in the context of the specific technique used. Current methods of thin section and rapid dynamic CT scanning allow more frequent identification of periampullary tumors.23Resectability is also better assessed by these methods. A recent study by Gulliver et alZ3demonstrated that thin section dynamic CT has a positive predictive value of 80% for determining resectability and a positive predictive value of 89% for determining unresectability of periampullary tumors. However, five patients in this study with unresectable tumors determined by thin section dynamic CT subsequently underwent operation, during which the tumors were deemed resectable. Since its introduction in 1968, ERCP has been crucial in the differential diagnosis of pancreatobiliary tumors.18Ampullary lesions are seen directly and may

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be biopsied with the endoscope. The biliary and pancreatic ducts are visualized by injection of contrast medium (Fig. 5 ) . Thus, obstruction or invasion of these ducts can be documented by ERCP. ERCP may be of great importance in determining the maximal extension of adenomatous changes along the bile duct or pancreatic duct. When used in conjunction with transpapillary cytology and biopsy, it is the most sensitive and specific procedure for the diagnosis of malignant ampullary tumors." However, it is unable to define accurately the extent of tumor invasion into the duodenal wall.44 The role of angiography in the preoperative evaluation of ampullary tumors is controversial. Angiography may help document portal and mesenteric vascular invasion and thereby indicate unresectability of some ampullary tumors, as in the preoperative assessment of pancreatic cancer. However, vascular invasion associated with ampullary tumors occurs with large bulky lesions, the resectability of which may be predicted by other methods. The preoperative delineation of arterial anatomy determined by angiography can be desirable, because anomalies are present in up to 24% of patients5"ut are not indispensable. New techniques of CT show great promise in producing images of the vascular anatomy sufficient to provide all of the same information in a much less invasive manner. EUS may have significant advantages over other imaging techniques in the evaluation of ampullary tumors. It provides transluminal cross-sectional images of the ampulla similar to CT scanning.35Images obtained by EUS have correlated

Figure 5. Endoscopic retrograde cholangiopancreatogram showing an ampullary tumor obstructing and extending into the biliary and pancreatic ducts. Such extension along the ductal system may preclude local excision of the ampullary tumor.

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with pathologic analysis and have been ~tandardized.~~ EUS can detect 96% to 100% of ampullary tumors, a record comparable to ERCP and better than US, CT, . ~addition, ~ EUS is more sensitive than US and CT at detecting or a n g i ~ g r a p h yIn small ampullary tumors and is capable of identifying tumors less than 10 mm in ~ize.4~ Whether EUS is more sensitive than direct visualizationat identifying small ampullary tumors is uncertain. In addition to the high rate of ampullary tumor detection associated with EUS, it appears to be the single most accurate technique for local ~ t a g i n g .The ~~,~~ overall accuracy in assessing ampullary tumor depth of invasion by EUS has been Both understaging and overstaging have been reapproximately 78% to 87%.44,51 ported.44Understaging results from microinvasion detected in resected specimens and from lymph node metastases that were not identified by EUS.44 The accuracy of EUS in detecting lymph node metastases is approximately 83%.44Conversely, the frequency of false-positive and false-negative lymph node "~~ high rate of falseassessment may be as high as 20% to 2 5 % ~ A~ relatively positive results occurs in association with inflammatory nodes, which are enlarged on EUS but are not infiltrated by carcinoma in subsequent pathologic analysis. EUS-guided aspiration of suspicious lymph nodes may prove to be valuable in the identification of malignant infiltration. EUS is also useful for assessing portal and mesenteric venous invasion associated with large ampullary tumors. In a recent study by Rosch et a1,5l the portal vein confluence was better assessed by EUS (95% accurate) than by angiography (85%),CT (75%),and abdominal US (55%).However, EUS was not as accurate as CT in evaluating the celiac axis and other distant sites. A study evaluating the accuracy of EUS in identifying portal venous invasion, conducted recently at our institution, demonstrated that EUS is highly sensitive for detecting portal and splenic vein invasion, but that it is disappointingly insensitive for identifying suIn 28 patients studied prospectively, the most perior mesenteric vein invol~ernent.~ accurate EUS criterion was irregularities of the venous wall (85%).Unfortunately, even this criterion suffered from a low sensitivity (40%),particularly because of difficulty in detecting it at the level of the superior mesenteric vein (sensitivityof 17%). In summary, EUS is clearly helpful in the surgical management of benign and early malignant ampullary tumors. Early stage malignant tumors have a frequency of associated lymph node metastases approaching 0%,36with a 5-year survival approaching EUS can distinguish early ampullary cancer from more advanced disease and may identify malignant lesions that are appropriate for local excision. However, it is limited in its ability to identify microscopic invasion, distant metastases, and superior mesenteric vein invasion and in differentiating inflammatory from malignant lymph nodes. Laparoscopy, which is widely applied to staging pancreatic cancer for the detection of small liver and peritoneal metastases not detected by imaging techniques or EUS, is not recommended for staging ampullary carcinomas because the yield of positive findings in this tumor system is only about 5%.74 AMPULLARY TUMORS: SURGICAL MANAGEMENT Historical Aspects Ampullary resection was first described by Halsted in 1899 and consisted of transduodenal excision of the ampulla, distal bile duct, and terminal pancreatic duct, with primary closure of the duodenum and reimplantation of the ducts into the duodenal wall.24This became the procedure of choice for ampullary neoplasms

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in the early part of the 20th but it was plagued by high rates of mortality and recurrence. Halsted's first patient died 7 months after the procedure as a result of tumor recurrence.'O The high rates of recurrence associated with the local excision of ampullary tumors prompted interest in more radical appro ache^.^^ Several investigators performed various radical resections during the first half of the century, culminating in Whipple's description of a two-stage pancreatoduodenectomy in 1935. Whipple's procedure, which was initially applied to a periampullary tumor, was subIt sequently used in the resection of pancreatic cancer by Brunschwig in 1937.10,57 was then converted to a one-stage operation by Trimble in 1941 and has since replaced local excision and become the most common procedure performed for the management ampullary and pancreatic m a l i g n a n c i e ~ . ~ ~ , ~ ~ Current Surgical Options

Options available for the surgical management of ampullary tumors include transduodenal local excision, pancreatoduodenectomy with or without pylorus preservation, and palliative bypass procedure^.^^ Selection from among the surgical options must be individualized because no one procedure is applicable to all lesions. Appropriate surgical management involves consideration of the size and nature of the ampullary tumor, the condition of the patient and associated illnesses, as well as the benefits of and potential problems associated with each procedure. The preoperative clinical assessment of ampullary tumors must be interpreted in the context of the limitations associated with the currently available diagnostic techniques. Indications for Local Excision

Transduodenal ampullectomy has traditionally been reserved for patients with benign ampullary tumors and for those with malignant tumors who were unable to tolerate radical resection. Benign tumors smaller than 3 cm are ideally suited for local excision, whereas tumors larger than 3 cm may require radical resection. Neuroendocrine tumors without malignant histologic features also may be considered for local excision, because they are often small and well circumscribed, including carcinoid, gastrinoma, somatostatinoma, and other islet cell tumors. Although 53% of ampullary carcinoid tumors smaller than 2 cm are assothey are most often indolent tumors, and high ciated with nodal metastase~?~ survival rates may be expected after local excision.I5However, large carcinoid tumors may require radical resection on the basis of size alone. Additionally, small cell neuroendocrine carcinomas appear to have a more aggressive clinical course than ampullary carcinoid tumorsI4 and may require pancreatoduodenectomy. Technique of Local Excision

The term local excision has described various techniques, from simple excision of the ampullary tumor and contiguous duodenal mucosa to wide resection of the mass, adjacent duodenum, intraduodenal bile duct, and terminal pancreatic duct.6 The technique of wide local excision used at our institution begins with general abdominal exploration followed by cholecystectomy, which allows easy identification of the ampulla via the common bile duct and prevents future gallbladder disease. This procedure is followed by wide mobilization of the duodenum. Pal-

pation of the ampullary lesion is usually possible through the wall of the duodenum and guides the placement of a longitudinal or transverse duodenotomy over the ampulla when the bile duct has not been cannulated previously. Stay sutures are placed in the edges of the duodenotomy, and the tumor is located and inspected (Fig. 6). Electrocautery is used to demarcate the resection borders circumferentially with a 1-cm margin of surrounding normal duodenal mucosa. With the tumor on traction, the dissection proceeds centripitally in the submucosal plane until the pancreatic and biliary ducts are encountered and transected. Placing 5 Fr catheters in the biliary and pancreatic ducts may facilitate their identification. As the tumor is excised, hemostasis is meticulously maintained to ensure adequate visability. The adequacy of the resection margins is evaluated by frozen section analysis, particularly of the pancreatic and biliary ducts. After adequate margins are confirmed, reconstruction proceeds with reapproximation of the biliary and pancreatic ducts and the formation of a common septum between the two ducts, using absorbable synthetic suture material (Fig. 7). A mucosa-to-mucosa anastomosis between the duodenum and ducts is then fashioned with interrupted 4-0 synthetic absorbable sutures. These sutures should include part of the duodenal muscularis in order to anchor the mucosal reconstruction and to minimize the potential for bleeding from the denuded surface. The bile duct orifice can be effectively enlarged by incising it along its cephalad margin and reapproximating the cut edge to the duodenum, as in a sphincteroplasty. Although the ducts are frequently dilated and do not require postoperative intubation or drainage, stents may be positioned within them and brought out through the common bile duct, third portion of the duodenum, or both. These stents are removed at least 10 days after the procedure. The duodenotomy is closed in a transverse fashion. If frozen section evaluation of the biliary and pancreatic ducts reveals tumor at the margins of resection, the excision must be extended, if possible, and the margins must be reassessed. Persistently positive margins at the limit of a recon-

Figure 6. lntraoperative view during local excision of an ampullary villous adenoma. The tumor is approached through a transverse duodenotomy and placed on traction. Electrocautery is used to demarcate a 1-cm rim of the normal surrounding duodenal mucosa, and the dissection is carried out in the submucosal plane.

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Figure 7. lntraoperative view of the pancreatic (open arrow) and biliary (solid arrow) ductal reconstruction after ampullectomy. A common septum is created by joining the adjacent walls

of the two ducts. Interrupted absorbable sutures (extending radially) are used to create a mucosa-to-mucosaanastomosis between the duodenum and ducts.

structable defect mandate conversion to pancreatoduodenectomy, for which the surgeon must be prepared. Local Excision Outcomes

Ampullectomy is associated with low rates of morbidity and mortality and is relatively easy to p e r f ~ r m . ' ~Rattner ,'~ et a1" recently reviewed 14 patients with ampullary tumors treated by local excision at the Massachusetts General Hospital and identified no deaths and only two complications (one delerium tremens and one delayed gastric emptying). The average length of hospital stay was 10 days, and no recurrences were present at a mean follow-up of 19 months. Other reports also have documented 0% perioperative mortality after ampullectomy for benign ampullary turn or^.^,^^,^^ Asbun et a16noted one death resulting from a pulmonary embolism after local excision. Other reported complications include postoperative , ~ pancreatic ab~cesses.~ ductal stricture^:^ i l e ~ sand Radical Resection: Indications and Outcomes

Since its description in 1935, radical resection in the form of pancreatoduodenectomy has generally been applied to the resection of ampullary cancer. Studies evaluating its role in ampullary cancer have demonstrated 5-year survival rates between 30% and 50%.29Our review of the literature since 1975 demonstrates an average 5-year survival rate of 38% after radical resection. Willett et a17'jevaluated our own institutional experience with 41 patients who underwent pancreatoduodenectomy for ampullary cancer and found an overall 5-year survival rate of 55% and 5-year local control rate of 69Y0.~"rnportantly, patients with "low risk"

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pathologic features (tumors limited to the ampulla or duodenum, well or moderately well differentiated histologic features, and uninvolved lymph nodes or resection margins) had 5-year survival and local control rates of 80% and 100%, respectively, whereas those patients with "high r i s k pathologic features (tumors invading the pancreas, poorly differentiated histologic features, involved lymph nodes or resection margins) had 5-year survival and local control rates of 38% and 50%, respectively. The impressive long-term survival rate after pancreatoduodenectomy is currently coupled with a less than 5% perioperative mortality.17The current standards of morbidity and mortality associated with pancreatoduodenectomy are significantly improved compared with the 1950s and 1960s.17In 1958, a single report documented a 51% operative mortality rate associated with pancreatoduodenectomy.17More recently, a review of pancreatic resections at the Massachusetts General Hospital reported no deaths in 142 consecutive pancreatoduodenectomies performed between 1991 and 1994.17Fifty-seven percent of these patients had no postoperative complications. Of the remaining patients, the incidence of delayed gastric emptying, major septic complications, and pancreatic fistulas were 11.2%, 12.6%, and 6.3%, respectively. The reoperation rate for any cause was only 1.5%. Pancreatic fistulas, which have traditionally caused most of the complications associated with pancreatoduodenectomy, were quite uncommon in this series and did not require any reoperations; all closed spontaneously. These low morbidity and mortality rates and those of other institutions support the continued use of pancreatoduodenectomy in T2 or more ampullary cancer. Radical resection also may be required in some patients with benign or premalignant tumors. The 4 to 5 cm duodenal defect that remains after the local excision of a 3-cm ampullary tumor is generally the upper size limit that can be reconstructed safely. This is true despite the presence of significant pancreatic or bile duct dilatation. Therefore, tumors larger than 3 cm require radical resection regardless of the histologic characteristics. Dysplastic ampullary adenomas in patients with FAP also should be considered for pancreatodu~denectomy.~~ In a recent study, 43% of patients with FAP who underwent local excision of ampullary adenomas with preoperative biopsies showing only moderate to severe atypia were found to have either carcinoma in situ or invasive cancer after excision.z7The potential for subsequent cancer development in the residual duodenum that remains after local excision is even more important than the high incidence of malignancy associated with the resected adenoma. These patients often have multiple polyps, and excision of the ampullary adenoma alone does not prevent the future development of malignancy. A 330-fold relative risk of duodenal cancer in patients with FAPZ8persists despite ampullectomy. In essence, ampullary tumors in patients with FAP may be thought of as diffusely spreading neoplasms or as tumors with field defects that warrant more aggressive resection. Endoscopic and Palliative Procedures

Cholecystoentericor choledochoentericbypass procedures provide palliative relief of biliary obstruction and have been recommended as alternatives to ampullary tumor removal.53Surgical bypass procedures also provide an opportunity to perform concomitant gastroenteric bypass," which may be necessary in some cases because of duodenal obstruction or bleeding. Such procedures are generally reserved for patients with unresectable tumors. The potential for GI bleeding persists when bypass procedures are performed without tumor suggesting that local or endoscopic resection of the ampullary tumor also should be performed if possible. If local excision or endoscopic resection is not feasible, endo-

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scopic stenting or sphincterotomy may provide at least palliative relief of pancreatic and biliary obstruction. Stents are successfully placed in more than 85% of patients, with a mortality rate of 1% to 2%.73 Endoscopic removal of small benign ampullary tumors is possible in some cases but may result in bleeding, perforation, or pan~reatitis~~; however, sessile tumors and large pendunculated tumors may not be amenable to this mode of excision.53Additionally, failure to obtain adequate resection margins may lead to tumor recurrence and may result in the missed~opportunity for curative r e ~ e c t i o n . ~ ~ Radiation Therapy

The role of adjuvant therapy in the treatment of ampullary cancer is not well defined. Small numbers of patients with ampullary tumors have precluded large scale prospective trials evaluating adjuvant chemotherapy and radiation treatment. However, retrospective studies suggest that adjuvant or neoadjuvant radiation therapy may improve outcomes in certain subgroups of patients with ampullary cancer. Twelve patients with high-risk features in Willett et a l ' ~ ~ ~ evaluation of ampullary cancer outcomes were treated with postoperative radiation therapy (40 Gy to 50.4 Gy in 22 to 28 of 1.8 Gy fractions during 5 to 6 weeks) and had a trend toward improved local control (83% local control with postoperative radiation versus 50% local control without it) but had no improvement in survival. Although the numbers were small in this subgroup of patients, distant metastases were common. This led Willett et a176to suggest that neoadjuvant radiation therapy given to patients with high-risk features might decrease the dissemination of metastatic cells during resection and in turn decrease the incidence .~~ patients with low-risk features who underwent of distant m e t a s t a ~ e s Because pancreatoduodenectomy only had 5-year survival and local control rates of 80% and loo%, respectively, adjuvant therapy does not appear to be necessary in all patients. Current Controversies

Recently, several investigators have advocated expanding the use of local excision to carefully selected premalignant and malignant tumors. Examples of such tumors include villous adenomas with severe dysplasia or with carcinoma in situ and even T1 ampullary cancer. Advocates of expanding the indications for local excision maintain that because TI ampullary cancer is unlikely to be assoit may ciated with lymph nodes metastases37and has a 100%5-year survival be excised without regard for regional lymphatic dissection. Such advocates also contend that ampullectomy is associated with low morbidity and mortality rates compared with pancreatoduodenectomy and should be preferred consequently. Anecdotal reports evaluating the application of local excision to patients with ampullary cancer who were unfit for pancreatoduodenectomy also support expanding its use. Such reports have surprisingly noted long-term survival rates that are similar to those of radical resection. Wise et a1,78Tarazi et al,67and Knox et a132each reported 5-year survival figures of 25%, 40%, and 51%, respectively after local excision. Of course, these results must be interpreted cautiously because they were obtained retrospectively by studies containing small patient numbers that did not define the criteria for selecting local excision nor describe the specific technique used. These caveats aside, the results are quite favorable. The ability to identify premalignant and malignant lesions that are amenable to local excision has improved significantly in the last few decades. Recent advances in the diagnostic evaluation of ampullary tumors discussed earlier, partic-

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ularly staging by EUS and transluminal biopsy techniques, now may identify such lesions and may help stratify patients appropriately into local excision or pancreatoduodenectomy. Pancreatic invasion is detected in most cases by current imaging methods, which help to avoid inappropriate application of local excision. Additionally, T3 and T4 ampullary carcinomas are easily differentiated from adenomas or early carcinoma. On the other hand, the preoperative assessment of ampullary tumors remains less than perfect despite recent improvements. Although EUS is the single most accurate method used in ampullary tumor staging, it also has failed to characterize some tumors accurately, a consequence of its inability to locate micrometastases Mukai et a144found one patient who was staged T1 by EUS and microin~asion.",~~ and who subsequently had T2 disease by pathologic analysis. Another two patients in the same series with NO disease characterized by EUS had N1 disease discovered after resection.@Although EUS may help identify most patients with premalignant and early malignant (stage I) ampullary tumors who may be appropriately treated by local excision, its limitations must be recognized, and the results should be evaluated in the context of other imaging studies, particularly ERCP. In addition to the potential staging errors associated with currently used imaging techniques, opponents of expanding the indications for local excision add a few other arguments. For instance, they protest that local excision inadequately resects known malignant disease and that preoperative evaluation often misdireview ~ ~ of duodenal villous agnoses malignant tumors as benign. Ryan et a l ' ~ adenomas at the Massachusetts General Hospital found that endoscopic biopsies failed to diagnose malignancy in 56% of tumors. Even intraoperative analysis may miss the diagnosis of cancer because frozen sections are associated with a falsenegative rate of SUMMARY AND FUTURE DIRECTIONS

The surgical management of benign and malignant ampullary tumors continues to evolve. Small benign ampullary tumors are appropriately treated by wide local excision. Radical resection in the form of pancreatoduodenectomy is clearly indicated in advanced malignant disease when it can be safely performed and may be applied to large benign ampullary tumors and to patients with FAP. Patients with invasive carcinoma who are unfit for radical resection should be considered for wide local excision or palliative bypass procedures. The optimal management of ampullary tumors occasionally requires deviation from these guidelines. Not all malignant tumors require pancreatoduodenectomy, and not all benign tumors are suitable for local excision. However, controversy exists regarding the application of local excision to premalignant and malignant ampullary tumors. Until prospective studies define subgroups of patients that are managed as well or better by local excision, it must be used cautiously in patients with such tumors. The decision to perform local excision in these patients must be individualized, with careful interpretation of the preoperative assessment. Surgeons also must be prepared to adjust the operative strategy based on the intraoperative findings and frozen section results. Regardless of the specific surgical approach used to manage patients with ampullary tumors, the most important technical consideration is the ability to obtain adequate resection margins. Although ampullary tumor surgery represents a relatively small fraction of GI procedures, it is of crucial importancebecause ampullary cancer may be the most curable of upper GI malignancies. Finally, the evolution of surgical approaches to ampullary tumors, which began in 1899, is ongoing and will continue as improvements in diagnostic and staging methods develop.

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