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PERIAMPULLARY CANCERS
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PERIAMPULLARY CANCERS Are There Differences? Juan M. Sarmiento, MD, David M. Nagorney, MD, Michael G. Sarr, MD, and Michael B. Famell, MD
By definition, periampullary cancers arise within 2 cm of the major papilla in the duodenum. They encompass four different types of cancers: ampullary (ampulla of Vater), biliary (intrapancreatic distal bile duct), pancreatic (headuncinate process), and duodenal (mainly from the second portion). Although these tumors have different origins, the complex regional anatomy and their proximation within that confined region generally dictate a common operative approach. Radical resections, such as the Whipple procedure or its variant with preservation of the pylorus with or without extended regional lymphadenectomy,58 have been the main treatments for these cancers, especially with the currently low morbidity and mortality rates.67Although the perioperative outcomes for these different cancers are similar, the long-term survival has traditionally varied. Consequently, because exact tumor origin is often difficult to clinically ascertain, surgeons have favored an aggressive approach toward resection to benefit those patients harboring cancers with a better prognosis. This observation has intrigued physicians managing patients with these cancers. It is unknown why outcome should vary for adenocarcinomas arising from different anatomic sites in such close proximity. Indeed, if survival does vary significantly for these cancers as clinical impression suggests, clearly, factors other than anatomy alone must be involved. This article explores whether there are differences in the clinical behavior of the periampullary cancers and defines which of these factors, if any, affect outcome. Moreover, it is important to determine which factors are valuable clinically so that they can be used to improve overall survival rates.
From the Department of Surgery, Mayo Clinic, Rochester, Minnesota
SURGICAL CLINICS OF NORTH AMERICA VOLUME 81 NUMBER 3 JUNE 2001
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Epidemiologic Considerations Prevalence Of Periampullary Cancers
Overall, periampullary cancers account for 5% of all gastrointestinal tract malignancies. Pancreatic cancer occurs most often among the periampullary cancers. They account for 3% of all gastrointestinal cancers. Cancers of the ampulla of Vater occur more frequently than distal common bile duct cancer with a ratio of l:lL5 In autopsy studies, the overall prevalence of periampullary cancers is between 0.063% and 0.21%.584z, 65 Considered separately, carcinoma of the ampulla of Vater has been observed in 0.2% of all routine autopsiesz7and represents less than 1% of all gastrointestinal tract malignancies;8 adenocarcinoma of the duodenum represents about 0.5% of all gastrointestinal malignancies" and is seen in less than 0.05% of autopsies.49 Importantly, surgeons should recognize that reports on operative results for individual periampullary cancers do not represent their actual incidence. Among resected periampullary cancers, cancer of the head of the pancreas accounts for 50% to 70%, ampullary cancer for 15% to 25%, biliary cancer for lo%, and duodenal cancer for These data reflect the prevalence of resected cancers. Importantly, these findings affect the analysis of surgical outcomes per se for pancreatoduodenectomy and emphasize the need to discriminate reported outcome by site of origin or specify cancer type. Clearly, if survival differs among periampullary cancers, reported outcomes for patients with periampullary cancers of heterogeneous origin will be somewhat biased. Inclusion of some patients with nonpancreatic periampullary cancers who survive 5 years among patients with pancreatic cancers who have a very low chance of 5-year survival can lead to an appreciably significant percentage increase in survival. SURVIVAL Outcome Studies Support Variable Survival
Representative outcome after pancreaticoduodenectomy for each type of periampullary cancers are shown in Tables 1 to 4. Overall perioperative morbidity and mortality for each cancer are similar. Overall perioperative mortality ranges from 0% to 15%. Overall perioperative morbidity also is similar among periampullary cancers and ranges from 30% to 50%. Postoperative diabetes after Whipple procedure is infrequent and does not occur more frequently with any of the periampullary cancers.' Overall survival of patients with resected periampullary cancers is also shown in Tables 1-4. Marked differences in overall survival are evident among patients with periampullary cancers. Overall 5-year survival is greatest for duodenal and ampullary cancers and least for pancreatic cancers, regardless of the recent reports of ostensibly improved perioperative survival for pancreatic cancers. Importantly, although the fundamental surgical approach (pancreaticoduodenectomy) has been similar among patients with these cancers, pancreaticoduodenectomy for pancreatic cancer is more frequently combined with neoadjuvant or adjuvant chemoirradiation or more extensive regional lymphadenectomy than for nonpancreatic periampullary cancers.13,l9 These data support the clinical contention that pancreatic cancer has the most clinically aggressive tumor biology of the periampullary cancers. Survival is greatest for ampullary and duodenal cancers and is intermediate for biliary cancers.
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Table 1. OUTCOME OF PATIENTS WITH PANCREATIC CANCER AFTER PANCREATICODUODENECTOMY
Study
Gall et a1 (1991)*17 Roder et a1 (1992)"" Geer et a1 (1993)"18 Klinkenbijl et a1 (1993)26 Tsao et a1 (1994)59 Wade et a1 (1995)60 Nitecki et a1 (1995y39 Ye0 et a1 (1995)66 Fortner et a (1996y Sperti et a1 (1996)*% Mosca et a1 (1997)*31 Zerbi et a1 (1998)" Neoptolemos et a1 (1997y3* Ye0 et a1 (1998)68
5-Year Survival Rate
Imo)
I%)
11 12
16 6
No. Pts
138 53
-
146
3
50
8
27
13
11
27 252
-
37
15
7 9
186
3
201 56
5 -
113
15
221
8
40
101
4
43
421
6
148
Operative Morbidity Rate I%)
Median Survival Time
Operative Mortality Rate (%)
6
8
24
7 18 -
26 14 12
16
8
12
15
'No adjuvant therapy.
ANATOMIC CONSIDERATIONS Embryology
Can the embryology of the specific anatomic sites of the periampullary region explain the perceived differences in cancer behavior? The caudal foregut and the cranial midgut generate the duodenum. The origin of the bile duct, the pancreas, and the ampulla of Vater arise from the foregut just above its junction with the midgut. By the end of the fourth week, the dorsal pancreatic primordium arises from the dorsal duodenal diverticulum. Concurrently, the ventral duodenal diverticulum differentiates into primitive liver cords, bile duct, and the ventral pancreas. The ventral pancreas later rotates to join the dorsal pancreas inferiorly and comprises the origin of the head of the pancreas and the uncinate process. The duct of the dorsal pancreas joins the ventral duct to form the duct of Wirsung, which empties into the major papilla. The dorsal pancreas may retain its original duct (accessory duct of Santorini),which empties in the minor papilla. Finally, the main pancreatic duct may fuse with the common bile duct. The common pancreaticobiliary channel of these fused ducts comprises the true ampulla of Vater. The ampulla is present only if a septum between the distal pancreatic and bile ducts does not extend to the tip of the papilla. A true
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Table 2. OUTCOME OF PATIENTS WITH DUCTAL BlLlARY TRACT CANCER AFTER PANCREATICODUODENECTOMY
Study
Nagorney et a1 (1993)”” Fong et a1 (1996)14 Kurosaki et a1 (1996)28 Nakeeb et a1 (1996)37 Wade et a1 (1997)61 Ye0 et a1 (1998)68 Zerbi et a1 (1998)7@ Takao et a1 (1999)57
No. Pts
Operative Mortality Rate (%)
Operative Morbidity Rate (%)
Median Survival Time (mo)
5-Year Survival Rate
22
5
24
-
43
39
4
33
33
27
-
20 73
1
30
11
33
30 27
4
35
-
30
22
22
22
27
22
13
58
32
Table 3. OUTCOME OF PATIENTS WITH AMPULLARY CANCER AFTER PANCREATICODUODENECTOMY
Study
Monson et a1 (1991)3@ Chareton et a1 (1996)8 Shirai et a1 (1996)52 Dorandeu et a1 (1997)”’ Nakai et a1 (1997)j5 Klempnauer et a1 (1998)25 Ye0 et a1 (1998)28 Beger et a1 (1999)5 Roberts et a1 (1999)45 Su et a1 (1999)56 *Repeat laparotomies.
No. Pts
Operative Mortality Rate (Yo)
104
Operative Morbidity Rate (%)
Median Survival Time (mo)
6*
5-Year Survival Rate
(“w 34
43
33
40
35
-
48
42
22
44
25
-
-
44
94
10
26*
38
46 88
-
-
3
25
49 -
39 42
32
9
59
-
46
13
15
48
38
33
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Table 4. OUTCOME OF PATIENTS WITH DUODENAL CANCER AFTER PANCREATICODUODENECTOMY
No. Study
PtS
Rose et a1 (1996)47 Sexe et a1 (1996)% Ohigashi et a1 (1998)40 S o h et a1 (1998)”” Ye0 et a1 (1998)68 Bakaeen et a1 (2000)4
38 34 24 35 17 50
Operative Mortality Rate (“h)
Operative Morbidity Rate (“h)
0 6 0 3 -
57 64
1
Median Survival Time (ma 86 -
-
-
5-Year Survival Rate
(“w
-60 32 57 67 59 54
ampulla is absent in nearly two thirds of patients. The dorsal mesentery of the duodenum resorbs later in fetal development and is replaced with loose avascular connective tissue. This plane is entered when performing the Kocher maneuver to expose the retropancreatic and retroduodenal regions. Embryologically and anatomically, patterns of periampullary cancer spread should be similar for pancreatic, ampullary, and distal bile duct cancers because they are foregut derivatives. In contrast, infra-ampullary duodenal cancers should spread primarily along the superior mesenteric or midgut pathways. Because of the ambiguous lymphatic drainage of the head of the pancreas, lymphatic metastases from pancreatic cancers are less predictable and are likely to extend along the foregut and midgut pathways. Invasion of the pancreas by nonpancreatic periampullary cancers likely predisposes to similar patterns of spread. Because most periampullary cancers arise commonly from the distal foregut, anatomic or embryologic factors likely contribute little to differences in outcome. PATHOLOGIC CONSIDERATIONS Outcome Influences: Histology and Other Factors
Accurate histologic classification of periampullary cancers can be notoriously difficult. Not uncommonly, careful pathologic review of resected specimens alters the original clinical diagnosis. Two practical points are useful in defining the origin of these cancers, which can significantly improve diagnostic clinical accuracy: (1)the predominant site of the mass of the cancer and (2) the presence of any component of carcinoma in situ. Nevertheless, some periampullary cancers will evade an unequivocal anatomic classification even after careful histopathologic review.’, 30 Periampullary cancers are derived from their respective epithelia, and almost all are adenocarcinoma. Substantial arguments support an adenoma-carcinoma sequence, at least for ampullary and duodenal 48 cancers, and probably some distal bile duct cancers. The frequency of malignancy in periampullary villous adenomas approaches 25% or greater? Duodenal cancers can be classified morphologically as polypoid, flat elevated, and ulcerative-invasive; ampullary and biliary cancers as papillary, nodular, and sclerosing. Regardless of origin, polypoid and papillary cancers have been associated with a better prognosis. The degree of cancer cell differentiation varies widely among the periampullary
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cancers and between individual cancers from each periampullary site. Undifferentiation (higher histopathologic grades) is typically greatest for pancreatic cancers and least for ampullary cancers. Undifferentiated (high-grade) histology has been frequently associated with a poorer prognosis than well-differentiated cancers, regardless of periampullary origin. Most periampullary cancers have a moderate grade histopathology. Several studies of periampullary cancers have explored markers of cancer biology. Genetic mutations and the presence of tumor markers could reveal similarities and differences in pathogenesis and could have prognostic implications. Zhu et a1 address similarities between duodenal and ampullary cancers.71 The expression of carcinoembryonic antigen (CEA), c-neu, p53, transforming growth factor (TGF), and epithelial membrane antigen (EMA) was analyzed. EMA was expressed in all duodenal and ampullary cancers, CEA in 73% of duodenal and in 63% of ampullary cancers, p53 in 20% of duodenal and 13% of ampullary cancers, and c-neu in 60% of duodenal and in 100% of ampullary cancers. The presence of c-neu correlated with shorter survival. These findings suggest some common pathways in the development of duodenal and ampullary cancers. Longnecker et aP9compared histologic findings between patients with histopathologically similar distal bile duct and pancreatic cancers. Neoplastic ductal epithelium had a similar range of differentiation. Desmoplasia was common in both cancers, and both cancers had a propensity for perineural invasion. Moreover, molecular and pathologic features of oncogene and tumor suppressor genes were similar and did not help differentiate between the two cancers. Ebert et a1 evaluated the presence of mutation on the K-ras oncogene, which has been traditionally expressed in more than 80% of pancreatic cancers." Using polymerase chain reaction techniques, they evaluated pancreatic cancers and their metastases, neuroendocrine tumors, cystadenomas, cystadenocarcinomas, and ampullary adenomas and adenocarcinoma. K-ras mutations at codon 12 were specific for pancreatic cancer; none of the other tumors showed this alteration. Ampullary cancers had mutations at codon 13. These data imply that specific K-ras gene mutations might play a role in the pathogenesis of pancreatic cancer. Friess et a1 recently compared some biomolecular features between pancreatic and ampullary cancers, which traditionally have different patterns of survival.I6Northern blot analysis, in situ hybridization, and immunohistochemistry were used to identify expression of epidermal growth factor receptor (EGFR), cerbB2, and c-erbB3. This EGFR family comprises four structurally homologous transmembrane proteins with intracellular tyrosine kinase activity. Enhanced expression of EGFR leads to malignant transformation, and receptor activation is associated with cell proliferation and tumor growth in cancer cells. These characteristics are shared by other members of this family. Although Northern blot analysis revealed comparable expression of messages for EGFR and cerbB2 mRNA in normal and cancerous ampullas, the message for c-erbB3 was significantly decreased in cancers. There was, however, no difference in expression of these three proteins by immunohistochemistry. In contrast, pancreatic cancer had enhanced expression of messages for EGFR, c-erbB2, and c-erbB3 and, in addition, greater immunostaining compared with normal pancreas. These findings strongly suggest a different molecular pathway in the development of ampullary and pancreatic cancers. The lack of upregulation of these growth factors in ampullary cancers could partly account for their less aggressive behavior (a different phenotype). Overall, these and other investigations addressing markers of tumor biology
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in periampullary cancers suggest that genetic differences between these cancers probably contribute significantly toward phenotypic differences and the perceived clinical differences among periampullary cancers. CLINICAL PRESENTATION
Clinical presentation often differs among patients with cancers primarily located in the distal portion of the biliary duct (biliary and ampullary), close to it (pancreatic), and those involving the ampullary complex, at least in early stages (duodenal). The main clinical difference is the timing of the onset of jaundice related to constitutional cancer symptoms. In patients in the former group, jaundice is always the most common symptom, and it usually precedes nausea, vomiting, or abdominal pain. With pancreatic cancers, jaundice is also common, but because the bile duct and ampullary region may not be involved early, jaundice occurs with a more advanced local progression. In patients with pancreatic cancer, the constitutional symptoms of abdominal pain, anemia, vomiting, and weight loss usually precede the onset of jaundice. Regardless of onset, jaundice should prompt a thorough and aggressive evaluation of the periampullary region. Although differences in clinical presentation between pancreatic and nonpancreatic periampullary cancers may exist, they are not clinically or prognostically significant. Moreover, although nonpancreatic periampullary cancers should present at an earlier stage, little data exist to support this hypothesis. Factors related to survival after resection have been sought for each periampullary cancer. A detailed list of these factors is beyond the scope of this article; however, tumor stage most consistently correlates with overall survival. Large tumor size and lymph node metastases adversely affect survival regardless of the origin of the periampullary cancer. As with overall survival, survival by each TNM stage for each cancer is greater for duodenal and ampullary cancers and least for pancreatic cancers. PREDICTORS OF SURVIVAL AMONG PERIAMPULLARY CANCERS Survival Differences versus Cancer Stage Local Growth Pattern
Early vs Late Jaundice. Intuitively, patients with cancers directly involving the distal bile duct should present with jaundice at an earlier stage of disease. Current data suggest that most ampullary, duodenal, and distal bile duct tumors present without lymph node metastases, and consequently when resected are associated with a better prognosis than pancreatic cancer. Although bile duct cancers should present early and should be associated with a prognosis equivalent to ampullary cancers, the fact that survival is not equivalent suggests that other tumor subtype factors are involved. Clearly, the T stage of pancreatic cancer that obstructs the bile duct by extension from the pancreatic duct with encasement or invasion must be more advanced than the other periampullary cancers. Factors. Focal growth patterns of the primary periampullary cancers likely contribute to outcome. Although initially all periampullary cancers arise intra-
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luminally from mucosa, subsequent invasion of duct or gut wall carries different implications. Intraluminal Growth. Biologic behavior among periampullary cancers is also manifested in their direction of growth. Intraluminal growth is present in 40% of ampullary cancers but in only 2% of pancreatic cancers and is followed by extraductal invasion in 60% of the ampullary cancers and 98% of the pancreatic cancers.ffiAdjacent tissue invasion represents advanced T stage of disease, and therefore, a poorer prognosis with an increased rate of invasion of lymphatic, venous, and perineural structures.ffiWhen any nonpancreatic periampullary cancer invades the pancreatic parenchyma, the prognosis decreases (similar to the pancreatic counterpart), and the frequency of lymphatic involvement increases significantlyzo,63 Invasion of ampullary cancers into the duodenal wall does not have the same adverse impact as does pancreatic invasion.25Clearly, pancreatic invasion or origin portends a poor prognosis." Similar findings for the relationship of T stage for duodenal cancers and prognosis have been Lymphatic and Neural Spread
Lymphatic Spread. Lymphatic metastases represent an advanced disease stage. In fact, some authors maintain that lymphatic invasion is equivalent to established lymphatic metastases. Pancreatic cancers present with lymph node metastases in 56% to 79% of patients, 9, 32, 36 ampullary cancers are associated with lymphatic metastases in 30% to 50%,3O and bile duct cancers in 56% to 69?'0.~~* ~ 3 ,69 The frequency of lymph node metastases is significantly increased when nonpancreatic periampullary cancers invade the pancreas, which is especially reflected in para-aortic lymph node metastases.= Ampullary tumors often have limited nodal involvement. These cancers usually involve the posterior pancreatoduodenal nodes ("first echelon")51and seldom the nodes located to the left of the superior mesenteric artery and the celiac ganglion.23In contrast, the nodal involvement in pancreatic cancer is more 32, 33 Shirai et a1 extensive and clearly involves both the above nodal showed an increased survival after pancreaticoduodenectomy and radical lymphadenectomy in ampullary tumors, which supports further evaluation of this aggressive approach even in the presence of lymphatic Duodenal tumors behave biologically differently than pancreatic cancers. There is 36% to 47% incidence of positive lymph nodes in pancreaticoduodenectomy specimens.Despite this frequency of nodal involvement, however, 5-year survival rate approaches 40% to 50%.47 In contrast, the presence of positive lymph nodes in patients with pancreatic cancer is associated with a 5-year survival of only 5Y0.'j8These findings justify a role for aggressive resection in duodenal and ampullary cancers, even in the presence of positive lymph 47
Perineural Invasion. Perineural invasion, especially extrapancreatically, is an important prognostic factor associated with pancreatobiliary tract cancer and generally connotes a poor prognosis. Most patients with pancreatic carcinoma have perineural invasion (concomitantly with lymphatic vessel invasion).41This feature of pancreatic cancer may contribute to the high incidence of local recurrence, especially retroperitoneally.In contrast, perineural invasion occurs in only 5% to 17% of patients with ampullary which has a lower local recurrence rate after resection. Interestingly, when perineural invasion is present with periampullary cancers, the prognosis is similar to pancreatic cancers.7,35 Finally, although bile duct cancers are associated with a high (86%)incidence of perineu-
PERIAMPULLARY CANCERS
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ral invasion, correlation with local recurrence has not been established because the frequency of positive postresection margins is a confounding f a ~ t o r ? ~ Molecular Concepts and Clinical Correlation. (See earlier discussion in Pathologic Considerations) Duodenal and ampullary tumors have the best prognosis among periampullary cancers. They are similar in their genesis; some ampullary cancers may arise from the duodenal type of epithelium and, hence, they share some of the steps of the molecular development model. This fact is evidenced in the data by Zhu et al, where some genes, tumor markers, and expression of growth factors are present in similar percentage in both cancers.71 Other genetic alterations, like the mutation of the K-ras oncogene, are almost exclusive to pancreatic cancers among the periampullary cancers.” Pancreatic cancers also express the receptor for EGFR, which is not expressed by other periampullary cancers and is associated with a much worse prognosis.16Finally, some histologic similarities were found between bile duct and pancreatic cancer~:~traditionally the ones with the worst outcome. Overall, it is impossible to point out a specific factor to explain the different outcomes of these cancers. The combinations of these features will ultimately determine the biologic behavior of each cancer. Stage at Initial Presentation. Size of primary tumor, tumor histologic differentiation, lymph node status, and resection margin status are very important when defining poor prognostic factors.68At presentation, pancreatic cancers have the highest frequency of these factors when compared with nonpancreatic periampullary ~ancers.6~ Of note, a higher incidence of positive margins after apparent curative resection in pancreatic cancer is a reflection of its usual early perineural invasion and accounts for its higher locoregional recurrence. The clinical correlation of decreased survival in pancreatic cancer is obvious after analyzing the data. ALTERNATIVE SURGICAL TREATMENT
Currently, pancreaticoduodenectomy (classic or pylorus-preserving) remains the treatment of choice for invasive periampullary cancer; however, more limited resections of nonpancreatic periampullary cancers have been used selectively because of patient infirmity from comorbidity, early cancer stage (Tis), or both. Some patients with small (1 cm) ampullary or distal bile duct cancers are candidates for transduodenal ampullectomy, and selected patients with duodenal cancers not involving the papilla or limited to the mucosa are candidates for partial duodenectomy or transduodenal excision. The role of ampullectomy in selected ampullary cancers is still controversial, despite improved T-staging through the use of endoscopic ultrasonography.44 Moreover, in 6% to 10% of patients with T1 cancers or carcinoma in situ harbor locoregional lymph node metastase~.~~ There are less risks of lymphatic metastases in well-differentiated cancers. If an adenoma has a component of carcinoma in situ or if the ampullary cancer is classified pT1 NO MO or welldifferentiated tumor (grade 1-2), then a transduodenal local excision is reason6, 24 Like ampullary able if the patient is unfit for pancreaticoduodenectomy.5~ cancers, well-differentiated TNM stage I duodenal cancers have been successfully treated using limited duodenectomy. Regardless of selection factors, overall survival is less for these approaches, and local recurrence rates exceed those reported for pancreatoduodenectomy.l2 After evaluating these cancers, perhaps ampullary cancers should be classified as duodenal cancers. The fact that two thirds of the population does not
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have ampulla of Vater? that the molecular development of both cancers follow the same process,71 and that clinical outcomes are similar regarding long-term survival (see Tables 3 and 4) strongly supports such a classification schema. This proposed single grouping of these two periampullary cancers subsequently would increase the population of patients under study and, consequently, increase the power in statistical analyses. SUMMARY
Our review supports the clinical impression that periampullary cancers vary in outcome after resection. Overall survival after pancreaticoduodenectomy is greatest for patients with ampullary and duodenal cancers, intermediate for patients with bile duct cancer, and least for patients with pancreatic cancer. Moreover, survival for each tumor stage is greater for nonpancreatic periampullary cancers than for pancreatic cancers. Invasion of the pancreas by nonpancreatic periampullary cancers is a major factor adversely affecting survival. Recent data suggest that inherent differences in tumor biology rather than embryologic, anatomic, or histologic factors probably account for these differences in survival. Finally, although pancreaticoduodenectomy remains the procedure of choice for resectable periampullary cancers, further increases in survival will likely evolve through more effective neoadjuvant or adjuvant therapies rather than modifications in the surgical approach. References 1. Andersen HB, Baden H, Brahe NE, et al: Pancreatoduodenectomy for periampullary
adenocarcinoma. J Am Coll Surg 179:545, 1994 2. Androulakis J, Colbom GL, Skandalakis PN, et al: Embryologic and anatomic basis of duodenal surgery. Surg Clin North Am 80171,2000 3. Baczako K, Buchler M, Kirkpatrick J, et al: Morphogenesis and possible precursor lesions of invasive carcinoma of the ampulla of Vater. Hum Patholl6305,1985 4. Bakaeen FG, Murr MM, Sarr MG, et al: What prognostic factors are important in duodenal adenocarcinoma? Arch Surg 135:635,2000 5. Beger HG, Treitschke F, Gansauge F, et al: Tumor of the ampulla of Vater. Arch Surg 134526, 1999 6. Bottger TC, Boddin J, Heintz A, et al: Clinicopathologic study for the assessment of resection for ampullary carcinoma. World J Surg 21:379, 1997 7. Cameron JL, Christ DW, Sitzmann JV,et al: Factors influencing survival after pancreatoduodenectomy for pancreatic cancer. Am J Surg 161:120, 1991 8. Chareton B, Coiffic J, Landen S, et a1 Diagnosis and therapy of ampullary tumors. World J Surg 20707,1996 9. Delcore R, Rodriguez FJ, Forster J, et al: Significance of lymph node metastases in patients with pancreatic cancer undergoing curative resection. Am J Surg 172:463,1996 10. Dorandeu A, Raoul JL, Siriser F, et al: Carcinoma of the ampulla of Vater: Prognostic factors after curative surgery: A series of 45 cases. Gut 40:350, 1997 11. B e r t MP, Hoffmann J, Schneider-Stock R, et al: Analysis of K-ras gene mutations in rare pancreatic and ampullary tumors. Eur J Gastroenterol Hepatol 10:1025, 1998 12. Fame11 M, Sakorafas GH, Sarr MG, et al: Villous tumors of the duodenum: Reappraisal of local vs. extended resection. Gastroenterology 116:A1310, 1999 13. Femandez-Cruz L, Johnson C, Dervenis C: Locoregional dissemination and extended lymphadenectomy in pancreatic cancer. Dig Surg 16313,1999 14. Fong Y, Blumgart LH, Lin E, et al: Outcome of treatment for distal bile duct cancer. Br J Surg 831712,1996
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15. Fortner JG, Klimstra DS, Seuie RT, et al: Tumor size is the primary prognosticator for pancreatic cancer after regional pancreatectomy. Ann Surg 223:147, 1996 16. Friess H. Wang I, Zhu Z , et al: Growth factor receptors are differently expressed in cancers of the papilla of Vater and pancreas. Ann Surg 230:767, 1999 17. Gall FP, Kessler H, Hermanek P: Surgical treatment of ductal pancreatic carcinoma. Eur J Surg Oncol 17173, 1991 18. Geer RJ, Brennan M F Prognostic indicators of survival after resection of pancreatic adenocarcinoma. Am J Surg 165:68, 1993 19. Ghanch P, Kawesha A, Howes N, et al: Adjuvant therapy for pancreatic cancer. World J Surg 23:937, 1999 20. Harada N, Treitschke F, Imaizumi T, et al: Pancreatic invasion is a prognostic indicator after radical resection for carcinoma of the ampulla of Vater. J Hepatobiliary-Pancreat Surg 4215, 1997 21. Kayahara M, Nagakawa T, Ohta T, et a1 Role of nodal involvement and the periductal soft tissue margin in middle and distal bile duct cancer. Ann Surg 1:76, 1999 22. Kayahara M, Nagakawa T, Ueno K, et a1 Lymphatic flow in carcinoma of the distal bile duct based on clinicopathological study. Cancer 72:2112, 1993 23. Kayahara M, Nagakawa T, Ueno K, et al: Surgical strategy for carcinoma of the pancreas head area based on clinicopathologic analysis on nodal involvement and plexus invasion. Surgery 117616, 1995 24. Klein P, Reingruber B, Kart1 S, et al: Is local excision of pT1-ampullary carcinomas justified? Eur J Oncol22:366, 1996 25. Klempnauer J, Ridder GJ, Maschek H, et a1 Carcinoma of the ampulla of Vater: Determinants of long-term survival in 94 resected patients. HPB Surg 11:1, 1998 26. Klinkenbijl JHG, Jeekel J, Schmitz PIM, et al: Carcinoma of the pancreas and periampullary region: Palliation versus cure. Br J Surg 80:1575, 1993 27. Knox RA, Kingston RD: Cancer of the ampulla of Vater. Br J Surg 73:72, 1986 28. Kurosaki I, Tsukada K, Hatakeyama K, et al: The mode of lymphatic spread in carcinoma of the bile duct. Am J Surg 172:239, 1996 29. Longnecker DS, Terhune PG: The case for parallel classification of biliary tract and pancreatic neoplasms. Mod Pathol9:828, 1996 30. Monson JR, Donohue JH, McEntee G: Radical resection for carcinoma of the ampulla of Vater. Arch Surg 126:353, 1991 31. Mosca F, Giulianotti PC, Balestracci T, et al: Long-term survival in pancreatic cancer: Pylorus-preserving versus Whipple pancreatoduodenectomy. Surgery 122:553, 1997 32. Nagakawa T, Kobayashi H, Ueno K, et al: Clinical study of lymphatic flow to the paraaortic lymph nodes in carcinoma of the head of the pancreas. Cancer 73:1155,1994 33. Nagakawa T, Konishi I, Ueno K, et al: A clinical study on lymphatic flow in carcinoma of the pancreatic head area-peripancreatic regional lymph node grouping. Hepatogastroenterology 40:457, 1993 34. Nagomey DM, Donohue JH, Fame11 MB, et al: Outcomes after curative resections of cholangiocarcinoma. Arch Surg 128:871, 1993 35. Nakai T, Koh K, Kawabe T, et al: Importance of microperineural invasion as a prognostic factor in ampullary carcinoma. Br J Surg 84:1399, 1997 36. Nakao A, Harada A, Nonami T, et al: Lymph node metastases in carcinoma of the head of the pancreas region. Br J Surg 82:399, 1995 37. Nakeeb A, Pitt HA, Sohn TA, et al: Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 224:463, 1996 38. Neoptolemos JP, Russel RCG, Bramhall S, et al: Low mortality following resection for pancreatic and periampullary tumors in 1026 patients: U.K. survey of specialist pancreatic units. Br J Surg 841370,1997 39. Nitecki SS, Sarr MG, Colby TV, et al: Long-term survival after resection for ductal adenocarcinoma of the pancreas: Is it really improving? Ann Surg 221:59, 1995 40. Ohigashi H, Ishikawa 0, Tamura S, et a1 Pancreatic invasion as the prognostic indicator of duodenal adenocarcinoma treated by pancreatoduodenectomy plus extended lymphadenectomy. Surgery 124:510, 1998 41. Ozaki H, Kinoshita T, Kosuge T, et al: Effectiveness of multimodality treatment for respectable pancreatic cancer. Int J Pancreatol 7195, 1990
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42. Perzin KH, Bridge M F Adenomas of the small intestine: A clinicopathologic review of 51 cases and a study of their relationship to carcinoma. Cancer 48:799, 1981 43. Pickelman J, Koelsch M, Cheifec G: Node-positive duodenal carcinoma is curable. Arch Surg 132241, 1997 44. Rattner DW, Femandez-del Castillo C, Brugge WR, et al: Defining the criteria for local resection of ampullary neoplasms. Arch Surg 131:266, 1996 45. Roberts RH, Krige JEJ, Bomman PC, et al: Pancreatoduodenectomy for ampullary carcinoma. Am Surg 65:1043, 1999 46. Roder JD, Stein HJ, Huttl W, et al: Pylorus-preserving versus standard pancreatoduodenectomy: An analysis of 110 pancreatic and periampullary carcinomas. R J Surg 79:152, 1992 47. Rose DM, Hochwald SN, Klimstra DS, et a1 Primary duodenal adenocarcinoma: a tenyear experience with 79 patients. J Am Coll Surg 183:89, 1996 48. Ryan PR, Schapiro RH, Warshaw AL: Villous tumors of the duodenum. Ann Surg 203:301, 1986 49. Sarma DP, Weilbacher TG: Adenocarcinoma of the duodenum. J Surg Oncol 34:262, 1987 50. Sexe RB, Wage TP, Virgo KS, et al: Incidence and treatment of periampullary duodenal cancer in the U.S. Veteran population. Cancer 77251, 1996 51. Shirai Y, Ohtani T, Tsukuda K, et al: Patterns of lymphatic spread of carcinoma of the ampulla of Vater. Br J Surg 841012, 1997 52. Shirai Y, Tsukada K, Ohtani T, et al: Carcinoma of the ampulla of Vater: is radical lymphadenectomy beneficial to patients with nodal disease? J Surg Oncol 61:190, 1996 53. Sohn TA, Lillemoe KD, Cameron JL, et al: Adenocarcinoma of the duodenum: Factors influencing long-term survival. J Gastrointest Surg 279, 1998 54. Sperti C, Pasquali C, Piccoli A, et a1 Survival after resection for ductal adenocarcinoma of the pancreas. Br J Surg 83:625, 1996 55. Spira IA, Ghazi A, Woll WI. Primary adenocarcinoma of the duodenum. Cancer 39:1721, 1977 56. Su CH, Shyr YM, Lui WY, et al: Factors affecting morbidity, mortality, and survival after pancreatoduodenectomy for carcinoma of the ampulla of Vater. Hepatogastroenterology 46:1973, 1999 57. Takao S, Shinchi H, Uchikura K, et al: Liver metastases after curative resection in patients with distal bile duct cancer. Br J Surg 86327, 1999 58. Traverso LW, Longmire WP Jr: Preservation of the pylorus in pancreatoduodenectomy. Surg Gynecol Obstet 146959, 1978 59. Tsao JI, Rossi RL, Lowell A Pylorus-preserving pancreatoduodenectomy. Is it an adequate cancer operation? Arch Surg 129:405,1994 60. Wade TP, El-Ghazzawy AG, Virgo KS, et a1 The Whipple resection for cancer in U.S. Department of Veteran Affairs Hospitals. Ann Surg 221:241, 1995 61. Wade TP, Prasad CN, Virgo KS, et al: Experience with distal bile duct cancers in US. Veterans Affairs Hospitals. J Surg Oncol 64:242, 1997 62. Whipple 0, Parsons WB, Mullins CR Treatment of carcinoma of the ampulla of Vater. Ann Surg 102763, 1935 63. Willett CG, Warshaw AL, Convery K, et al: Patterns of failure after pancreatoduodenectomy for ampullary carcinoma. Surg Gynecol Obstet 176:33, 1993 64. Yamaguchi K, Enjoji M, Tsuneyoshi M Pancreatoduodenal carcinoma: a clinicopathologic study of 304 patients and immunohistochemical observation for CEA and CA 19-9. J Surg Oncol47148, 1991 65. Yamaguchi K, Enjoji M: Carcinoma of the ampulla of Vater: A clinicopathologic study and pathologic staging of 109 cases of carcinoma and 5 cases of adenoma. Cancer 59:506, 1987 66. Ye0 CJ, Cameron JL, Lillemoe KD, et al: Pancreatoduodenectomy for cancer of the head of the pancreas: 201 patients. Ann Surg 221:721, 1995 67. Ye0 CJ, Cameron JL, Sohn TA, et al: Six hundred fifty consecutive pancreatoduodenectomies in the 1990s: Pathology, complications, and outcomes. Ann Surg 226248, 1997 68. Ye0 CJ, S o h TA, Cameron JL, et al: Periampullary adenocarcinoma. Analysis of 5year survivors. Ann Surg 2278921, 1998
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69. Yoshida T, Shibata K, Yokoyama H, et a1 Patterns of node metastasis in carcinoma of the distal bile duct. Hepatogastroenterology 461595, 1999 70. Zerbi A, Balzano G, Leone BE, et a1 Clinical presentation, diagnosis, and survival of resected distal bile duct cancer. Dig Surg 15:410, 1998 71. Zhu L, Kim K, Comenico DR, et al: Adenocarcinoma of the duodenum and ampulla of Vater: Clinicopathology study and expression of p53, c-neu, TGF, CEA, and EMA. J Surg Oncol61:100, 1996
Address reprint requests to David M. Nagomey, MD Mayo Clinic 200 First Street SW Rochester, MN 55905
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PERIAMPULLARY CANCERS Are There Differences? Juan M. Sarmiento, MD, David M. Nagorney, MD, Michael G. Sarr, MD, and Michael B. Famell, MD
By definition, periampullary cancers arise within 2 cm of the major papilla in the duodenum. They encompass four different types of cancers: ampullary (ampulla of Vater), biliary (intrapancreatic distal bile duct), pancreatic (headuncinate process), and duodenal (mainly from the second portion). Although these tumors have different origins, the complex regional anatomy and their proximation within that confined region generally dictate a common operative approach. Radical resections, such as the Whipple procedure or its variant with preservation of the pylorus with or without extended regional lymphadenectomy,58 have been the main treatments for these cancers, especially with the currently low morbidity and mortality rates.67Although the perioperative outcomes for these different cancers are similar, the long-term survival has traditionally varied. Consequently, because exact tumor origin is often difficult to clinically ascertain, surgeons have favored an aggressive approach toward resection to benefit those patients harboring cancers with a better prognosis. This observation has intrigued physicians managing patients with these cancers. It is unknown why outcome should vary for adenocarcinomas arising from different anatomic sites in such close proximity. Indeed, if survival does vary significantly for these cancers as clinical impression suggests, clearly, factors other than anatomy alone must be involved. This article explores whether there are differences in the clinical behavior of the periampullary cancers and defines which of these factors, if any, affect outcome. Moreover, it is important to determine which factors are valuable clinically so that they can be used to improve overall survival rates.
From the Department of Surgery, Mayo Clinic, Rochester, Minnesota
SURGICAL CLINICS OF NORTH AMERICA VOLUME 81 NUMBER 3 JUNE 2001
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Epidemiologic Considerations Prevalence Of Periampullary Cancers
Overall, periampullary cancers account for 5% of all gastrointestinal tract malignancies. Pancreatic cancer occurs most often among the periampullary cancers. They account for 3% of all gastrointestinal cancers. Cancers of the ampulla of Vater occur more frequently than distal common bile duct cancer with a ratio of l:lL5 In autopsy studies, the overall prevalence of periampullary cancers is between 0.063% and 0.21%.584z, 65 Considered separately, carcinoma of the ampulla of Vater has been observed in 0.2% of all routine autopsiesz7and represents less than 1% of all gastrointestinal tract malignancies;8 adenocarcinoma of the duodenum represents about 0.5% of all gastrointestinal malignancies" and is seen in less than 0.05% of autopsies.49 Importantly, surgeons should recognize that reports on operative results for individual periampullary cancers do not represent their actual incidence. Among resected periampullary cancers, cancer of the head of the pancreas accounts for 50% to 70%, ampullary cancer for 15% to 25%, biliary cancer for lo%, and duodenal cancer for These data reflect the prevalence of resected cancers. Importantly, these findings affect the analysis of surgical outcomes per se for pancreatoduodenectomy and emphasize the need to discriminate reported outcome by site of origin or specify cancer type. Clearly, if survival differs among periampullary cancers, reported outcomes for patients with periampullary cancers of heterogeneous origin will be somewhat biased. Inclusion of some patients with nonpancreatic periampullary cancers who survive 5 years among patients with pancreatic cancers who have a very low chance of 5-year survival can lead to an appreciably significant percentage increase in survival. SURVIVAL Outcome Studies Support Variable Survival
Representative outcome after pancreaticoduodenectomy for each type of periampullary cancers are shown in Tables 1 to 4. Overall perioperative morbidity and mortality for each cancer are similar. Overall perioperative mortality ranges from 0% to 15%. Overall perioperative morbidity also is similar among periampullary cancers and ranges from 30% to 50%. Postoperative diabetes after Whipple procedure is infrequent and does not occur more frequently with any of the periampullary cancers.' Overall survival of patients with resected periampullary cancers is also shown in Tables 1-4. Marked differences in overall survival are evident among patients with periampullary cancers. Overall 5-year survival is greatest for duodenal and ampullary cancers and least for pancreatic cancers, regardless of the recent reports of ostensibly improved perioperative survival for pancreatic cancers. Importantly, although the fundamental surgical approach (pancreaticoduodenectomy) has been similar among patients with these cancers, pancreaticoduodenectomy for pancreatic cancer is more frequently combined with neoadjuvant or adjuvant chemoirradiation or more extensive regional lymphadenectomy than for nonpancreatic periampullary cancers.13,l9 These data support the clinical contention that pancreatic cancer has the most clinically aggressive tumor biology of the periampullary cancers. Survival is greatest for ampullary and duodenal cancers and is intermediate for biliary cancers.
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Table 1. OUTCOME OF PATIENTS WITH PANCREATIC CANCER AFTER PANCREATICODUODENECTOMY
Study
Gall et a1 (1991)*17 Roder et a1 (1992)"" Geer et a1 (1993)"18 Klinkenbijl et a1 (1993)26 Tsao et a1 (1994)59 Wade et a1 (1995)60 Nitecki et a1 (1995y39 Ye0 et a1 (1995)66 Fortner et a (1996y Sperti et a1 (1996)*% Mosca et a1 (1997)*31 Zerbi et a1 (1998)" Neoptolemos et a1 (1997y3* Ye0 et a1 (1998)68
5-Year Survival Rate
Imo)
I%)
11 12
16 6
No. Pts
138 53
-
146
3
50
8
27
13
11
27 252
-
37
15
7 9
186
3
201 56
5 -
113
15
221
8
40
101
4
43
421
6
148
Operative Morbidity Rate I%)
Median Survival Time
Operative Mortality Rate (%)
6
8
24
7 18 -
26 14 12
16
8
12
15
'No adjuvant therapy.
ANATOMIC CONSIDERATIONS Embryology
Can the embryology of the specific anatomic sites of the periampullary region explain the perceived differences in cancer behavior? The caudal foregut and the cranial midgut generate the duodenum. The origin of the bile duct, the pancreas, and the ampulla of Vater arise from the foregut just above its junction with the midgut. By the end of the fourth week, the dorsal pancreatic primordium arises from the dorsal duodenal diverticulum. Concurrently, the ventral duodenal diverticulum differentiates into primitive liver cords, bile duct, and the ventral pancreas. The ventral pancreas later rotates to join the dorsal pancreas inferiorly and comprises the origin of the head of the pancreas and the uncinate process. The duct of the dorsal pancreas joins the ventral duct to form the duct of Wirsung, which empties into the major papilla. The dorsal pancreas may retain its original duct (accessory duct of Santorini),which empties in the minor papilla. Finally, the main pancreatic duct may fuse with the common bile duct. The common pancreaticobiliary channel of these fused ducts comprises the true ampulla of Vater. The ampulla is present only if a septum between the distal pancreatic and bile ducts does not extend to the tip of the papilla. A true
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Table 2. OUTCOME OF PATIENTS WITH DUCTAL BlLlARY TRACT CANCER AFTER PANCREATICODUODENECTOMY
Study
Nagorney et a1 (1993)”” Fong et a1 (1996)14 Kurosaki et a1 (1996)28 Nakeeb et a1 (1996)37 Wade et a1 (1997)61 Ye0 et a1 (1998)68 Zerbi et a1 (1998)7@ Takao et a1 (1999)57
No. Pts
Operative Mortality Rate (%)
Operative Morbidity Rate (%)
Median Survival Time (mo)
5-Year Survival Rate
22
5
24
-
43
39
4
33
33
27
-
20 73
1
30
11
33
30 27
4
35
-
30
22
22
22
27
22
13
58
32
Table 3. OUTCOME OF PATIENTS WITH AMPULLARY CANCER AFTER PANCREATICODUODENECTOMY
Study
Monson et a1 (1991)3@ Chareton et a1 (1996)8 Shirai et a1 (1996)52 Dorandeu et a1 (1997)”’ Nakai et a1 (1997)j5 Klempnauer et a1 (1998)25 Ye0 et a1 (1998)28 Beger et a1 (1999)5 Roberts et a1 (1999)45 Su et a1 (1999)56 *Repeat laparotomies.
No. Pts
Operative Mortality Rate (Yo)
104
Operative Morbidity Rate (%)
Median Survival Time (mo)
6*
5-Year Survival Rate
(“w 34
43
33
40
35
-
48
42
22
44
25
-
-
44
94
10
26*
38
46 88
-
-
3
25
49 -
39 42
32
9
59
-
46
13
15
48
38
33
PERIAMPULLARY CANCERS
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Table 4. OUTCOME OF PATIENTS WITH DUODENAL CANCER AFTER PANCREATICODUODENECTOMY
No. Study
PtS
Rose et a1 (1996)47 Sexe et a1 (1996)% Ohigashi et a1 (1998)40 S o h et a1 (1998)”” Ye0 et a1 (1998)68 Bakaeen et a1 (2000)4
38 34 24 35 17 50
Operative Mortality Rate (“h)
Operative Morbidity Rate (“h)
0 6 0 3 -
57 64
1
Median Survival Time (ma 86 -
-
-
5-Year Survival Rate
(“w
-60 32 57 67 59 54
ampulla is absent in nearly two thirds of patients. The dorsal mesentery of the duodenum resorbs later in fetal development and is replaced with loose avascular connective tissue. This plane is entered when performing the Kocher maneuver to expose the retropancreatic and retroduodenal regions. Embryologically and anatomically, patterns of periampullary cancer spread should be similar for pancreatic, ampullary, and distal bile duct cancers because they are foregut derivatives. In contrast, infra-ampullary duodenal cancers should spread primarily along the superior mesenteric or midgut pathways. Because of the ambiguous lymphatic drainage of the head of the pancreas, lymphatic metastases from pancreatic cancers are less predictable and are likely to extend along the foregut and midgut pathways. Invasion of the pancreas by nonpancreatic periampullary cancers likely predisposes to similar patterns of spread. Because most periampullary cancers arise commonly from the distal foregut, anatomic or embryologic factors likely contribute little to differences in outcome. PATHOLOGIC CONSIDERATIONS Outcome Influences: Histology and Other Factors
Accurate histologic classification of periampullary cancers can be notoriously difficult. Not uncommonly, careful pathologic review of resected specimens alters the original clinical diagnosis. Two practical points are useful in defining the origin of these cancers, which can significantly improve diagnostic clinical accuracy: (1)the predominant site of the mass of the cancer and (2) the presence of any component of carcinoma in situ. Nevertheless, some periampullary cancers will evade an unequivocal anatomic classification even after careful histopathologic review.’, 30 Periampullary cancers are derived from their respective epithelia, and almost all are adenocarcinoma. Substantial arguments support an adenoma-carcinoma sequence, at least for ampullary and duodenal 48 cancers, and probably some distal bile duct cancers. The frequency of malignancy in periampullary villous adenomas approaches 25% or greater? Duodenal cancers can be classified morphologically as polypoid, flat elevated, and ulcerative-invasive; ampullary and biliary cancers as papillary, nodular, and sclerosing. Regardless of origin, polypoid and papillary cancers have been associated with a better prognosis. The degree of cancer cell differentiation varies widely among the periampullary
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cancers and between individual cancers from each periampullary site. Undifferentiation (higher histopathologic grades) is typically greatest for pancreatic cancers and least for ampullary cancers. Undifferentiated (high-grade) histology has been frequently associated with a poorer prognosis than well-differentiated cancers, regardless of periampullary origin. Most periampullary cancers have a moderate grade histopathology. Several studies of periampullary cancers have explored markers of cancer biology. Genetic mutations and the presence of tumor markers could reveal similarities and differences in pathogenesis and could have prognostic implications. Zhu et a1 address similarities between duodenal and ampullary cancers.71 The expression of carcinoembryonic antigen (CEA), c-neu, p53, transforming growth factor (TGF), and epithelial membrane antigen (EMA) was analyzed. EMA was expressed in all duodenal and ampullary cancers, CEA in 73% of duodenal and in 63% of ampullary cancers, p53 in 20% of duodenal and 13% of ampullary cancers, and c-neu in 60% of duodenal and in 100% of ampullary cancers. The presence of c-neu correlated with shorter survival. These findings suggest some common pathways in the development of duodenal and ampullary cancers. Longnecker et aP9compared histologic findings between patients with histopathologically similar distal bile duct and pancreatic cancers. Neoplastic ductal epithelium had a similar range of differentiation. Desmoplasia was common in both cancers, and both cancers had a propensity for perineural invasion. Moreover, molecular and pathologic features of oncogene and tumor suppressor genes were similar and did not help differentiate between the two cancers. Ebert et a1 evaluated the presence of mutation on the K-ras oncogene, which has been traditionally expressed in more than 80% of pancreatic cancers." Using polymerase chain reaction techniques, they evaluated pancreatic cancers and their metastases, neuroendocrine tumors, cystadenomas, cystadenocarcinomas, and ampullary adenomas and adenocarcinoma. K-ras mutations at codon 12 were specific for pancreatic cancer; none of the other tumors showed this alteration. Ampullary cancers had mutations at codon 13. These data imply that specific K-ras gene mutations might play a role in the pathogenesis of pancreatic cancer. Friess et a1 recently compared some biomolecular features between pancreatic and ampullary cancers, which traditionally have different patterns of survival.I6Northern blot analysis, in situ hybridization, and immunohistochemistry were used to identify expression of epidermal growth factor receptor (EGFR), cerbB2, and c-erbB3. This EGFR family comprises four structurally homologous transmembrane proteins with intracellular tyrosine kinase activity. Enhanced expression of EGFR leads to malignant transformation, and receptor activation is associated with cell proliferation and tumor growth in cancer cells. These characteristics are shared by other members of this family. Although Northern blot analysis revealed comparable expression of messages for EGFR and cerbB2 mRNA in normal and cancerous ampullas, the message for c-erbB3 was significantly decreased in cancers. There was, however, no difference in expression of these three proteins by immunohistochemistry. In contrast, pancreatic cancer had enhanced expression of messages for EGFR, c-erbB2, and c-erbB3 and, in addition, greater immunostaining compared with normal pancreas. These findings strongly suggest a different molecular pathway in the development of ampullary and pancreatic cancers. The lack of upregulation of these growth factors in ampullary cancers could partly account for their less aggressive behavior (a different phenotype). Overall, these and other investigations addressing markers of tumor biology
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in periampullary cancers suggest that genetic differences between these cancers probably contribute significantly toward phenotypic differences and the perceived clinical differences among periampullary cancers. CLINICAL PRESENTATION
Clinical presentation often differs among patients with cancers primarily located in the distal portion of the biliary duct (biliary and ampullary), close to it (pancreatic), and those involving the ampullary complex, at least in early stages (duodenal). The main clinical difference is the timing of the onset of jaundice related to constitutional cancer symptoms. In patients in the former group, jaundice is always the most common symptom, and it usually precedes nausea, vomiting, or abdominal pain. With pancreatic cancers, jaundice is also common, but because the bile duct and ampullary region may not be involved early, jaundice occurs with a more advanced local progression. In patients with pancreatic cancer, the constitutional symptoms of abdominal pain, anemia, vomiting, and weight loss usually precede the onset of jaundice. Regardless of onset, jaundice should prompt a thorough and aggressive evaluation of the periampullary region. Although differences in clinical presentation between pancreatic and nonpancreatic periampullary cancers may exist, they are not clinically or prognostically significant. Moreover, although nonpancreatic periampullary cancers should present at an earlier stage, little data exist to support this hypothesis. Factors related to survival after resection have been sought for each periampullary cancer. A detailed list of these factors is beyond the scope of this article; however, tumor stage most consistently correlates with overall survival. Large tumor size and lymph node metastases adversely affect survival regardless of the origin of the periampullary cancer. As with overall survival, survival by each TNM stage for each cancer is greater for duodenal and ampullary cancers and least for pancreatic cancers. PREDICTORS OF SURVIVAL AMONG PERIAMPULLARY CANCERS Survival Differences versus Cancer Stage Local Growth Pattern
Early vs Late Jaundice. Intuitively, patients with cancers directly involving the distal bile duct should present with jaundice at an earlier stage of disease. Current data suggest that most ampullary, duodenal, and distal bile duct tumors present without lymph node metastases, and consequently when resected are associated with a better prognosis than pancreatic cancer. Although bile duct cancers should present early and should be associated with a prognosis equivalent to ampullary cancers, the fact that survival is not equivalent suggests that other tumor subtype factors are involved. Clearly, the T stage of pancreatic cancer that obstructs the bile duct by extension from the pancreatic duct with encasement or invasion must be more advanced than the other periampullary cancers. Factors. Focal growth patterns of the primary periampullary cancers likely contribute to outcome. Although initially all periampullary cancers arise intra-
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luminally from mucosa, subsequent invasion of duct or gut wall carries different implications. Intraluminal Growth. Biologic behavior among periampullary cancers is also manifested in their direction of growth. Intraluminal growth is present in 40% of ampullary cancers but in only 2% of pancreatic cancers and is followed by extraductal invasion in 60% of the ampullary cancers and 98% of the pancreatic cancers.ffiAdjacent tissue invasion represents advanced T stage of disease, and therefore, a poorer prognosis with an increased rate of invasion of lymphatic, venous, and perineural structures.ffiWhen any nonpancreatic periampullary cancer invades the pancreatic parenchyma, the prognosis decreases (similar to the pancreatic counterpart), and the frequency of lymphatic involvement increases significantlyzo,63 Invasion of ampullary cancers into the duodenal wall does not have the same adverse impact as does pancreatic invasion.25Clearly, pancreatic invasion or origin portends a poor prognosis." Similar findings for the relationship of T stage for duodenal cancers and prognosis have been Lymphatic and Neural Spread
Lymphatic Spread. Lymphatic metastases represent an advanced disease stage. In fact, some authors maintain that lymphatic invasion is equivalent to established lymphatic metastases. Pancreatic cancers present with lymph node metastases in 56% to 79% of patients, 9, 32, 36 ampullary cancers are associated with lymphatic metastases in 30% to 50%,3O and bile duct cancers in 56% to 69?'0.~~* ~ 3 ,69 The frequency of lymph node metastases is significantly increased when nonpancreatic periampullary cancers invade the pancreas, which is especially reflected in para-aortic lymph node metastases.= Ampullary tumors often have limited nodal involvement. These cancers usually involve the posterior pancreatoduodenal nodes ("first echelon")51and seldom the nodes located to the left of the superior mesenteric artery and the celiac ganglion.23In contrast, the nodal involvement in pancreatic cancer is more 32, 33 Shirai et a1 extensive and clearly involves both the above nodal showed an increased survival after pancreaticoduodenectomy and radical lymphadenectomy in ampullary tumors, which supports further evaluation of this aggressive approach even in the presence of lymphatic Duodenal tumors behave biologically differently than pancreatic cancers. There is 36% to 47% incidence of positive lymph nodes in pancreaticoduodenectomy specimens.Despite this frequency of nodal involvement, however, 5-year survival rate approaches 40% to 50%.47 In contrast, the presence of positive lymph nodes in patients with pancreatic cancer is associated with a 5-year survival of only 5Y0.'j8These findings justify a role for aggressive resection in duodenal and ampullary cancers, even in the presence of positive lymph 47
Perineural Invasion. Perineural invasion, especially extrapancreatically, is an important prognostic factor associated with pancreatobiliary tract cancer and generally connotes a poor prognosis. Most patients with pancreatic carcinoma have perineural invasion (concomitantly with lymphatic vessel invasion).41This feature of pancreatic cancer may contribute to the high incidence of local recurrence, especially retroperitoneally.In contrast, perineural invasion occurs in only 5% to 17% of patients with ampullary which has a lower local recurrence rate after resection. Interestingly, when perineural invasion is present with periampullary cancers, the prognosis is similar to pancreatic cancers.7,35 Finally, although bile duct cancers are associated with a high (86%)incidence of perineu-
PERIAMPULLARY CANCERS
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ral invasion, correlation with local recurrence has not been established because the frequency of positive postresection margins is a confounding f a ~ t o r ? ~ Molecular Concepts and Clinical Correlation. (See earlier discussion in Pathologic Considerations) Duodenal and ampullary tumors have the best prognosis among periampullary cancers. They are similar in their genesis; some ampullary cancers may arise from the duodenal type of epithelium and, hence, they share some of the steps of the molecular development model. This fact is evidenced in the data by Zhu et al, where some genes, tumor markers, and expression of growth factors are present in similar percentage in both cancers.71 Other genetic alterations, like the mutation of the K-ras oncogene, are almost exclusive to pancreatic cancers among the periampullary cancers.” Pancreatic cancers also express the receptor for EGFR, which is not expressed by other periampullary cancers and is associated with a much worse prognosis.16Finally, some histologic similarities were found between bile duct and pancreatic cancer~:~traditionally the ones with the worst outcome. Overall, it is impossible to point out a specific factor to explain the different outcomes of these cancers. The combinations of these features will ultimately determine the biologic behavior of each cancer. Stage at Initial Presentation. Size of primary tumor, tumor histologic differentiation, lymph node status, and resection margin status are very important when defining poor prognostic factors.68At presentation, pancreatic cancers have the highest frequency of these factors when compared with nonpancreatic periampullary ~ancers.6~ Of note, a higher incidence of positive margins after apparent curative resection in pancreatic cancer is a reflection of its usual early perineural invasion and accounts for its higher locoregional recurrence. The clinical correlation of decreased survival in pancreatic cancer is obvious after analyzing the data. ALTERNATIVE SURGICAL TREATMENT
Currently, pancreaticoduodenectomy (classic or pylorus-preserving) remains the treatment of choice for invasive periampullary cancer; however, more limited resections of nonpancreatic periampullary cancers have been used selectively because of patient infirmity from comorbidity, early cancer stage (Tis), or both. Some patients with small (1 cm) ampullary or distal bile duct cancers are candidates for transduodenal ampullectomy, and selected patients with duodenal cancers not involving the papilla or limited to the mucosa are candidates for partial duodenectomy or transduodenal excision. The role of ampullectomy in selected ampullary cancers is still controversial, despite improved T-staging through the use of endoscopic ultrasonography.44 Moreover, in 6% to 10% of patients with T1 cancers or carcinoma in situ harbor locoregional lymph node metastase~.~~ There are less risks of lymphatic metastases in well-differentiated cancers. If an adenoma has a component of carcinoma in situ or if the ampullary cancer is classified pT1 NO MO or welldifferentiated tumor (grade 1-2), then a transduodenal local excision is reason6, 24 Like ampullary able if the patient is unfit for pancreaticoduodenectomy.5~ cancers, well-differentiated TNM stage I duodenal cancers have been successfully treated using limited duodenectomy. Regardless of selection factors, overall survival is less for these approaches, and local recurrence rates exceed those reported for pancreatoduodenectomy.l2 After evaluating these cancers, perhaps ampullary cancers should be classified as duodenal cancers. The fact that two thirds of the population does not
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have ampulla of Vater? that the molecular development of both cancers follow the same process,71 and that clinical outcomes are similar regarding long-term survival (see Tables 3 and 4) strongly supports such a classification schema. This proposed single grouping of these two periampullary cancers subsequently would increase the population of patients under study and, consequently, increase the power in statistical analyses. SUMMARY
Our review supports the clinical impression that periampullary cancers vary in outcome after resection. Overall survival after pancreaticoduodenectomy is greatest for patients with ampullary and duodenal cancers, intermediate for patients with bile duct cancer, and least for patients with pancreatic cancer. Moreover, survival for each tumor stage is greater for nonpancreatic periampullary cancers than for pancreatic cancers. Invasion of the pancreas by nonpancreatic periampullary cancers is a major factor adversely affecting survival. Recent data suggest that inherent differences in tumor biology rather than embryologic, anatomic, or histologic factors probably account for these differences in survival. Finally, although pancreaticoduodenectomy remains the procedure of choice for resectable periampullary cancers, further increases in survival will likely evolve through more effective neoadjuvant or adjuvant therapies rather than modifications in the surgical approach. References 1. Andersen HB, Baden H, Brahe NE, et al: Pancreatoduodenectomy for periampullary
adenocarcinoma. J Am Coll Surg 179:545, 1994 2. Androulakis J, Colbom GL, Skandalakis PN, et al: Embryologic and anatomic basis of duodenal surgery. Surg Clin North Am 80171,2000 3. Baczako K, Buchler M, Kirkpatrick J, et al: Morphogenesis and possible precursor lesions of invasive carcinoma of the ampulla of Vater. Hum Patholl6305,1985 4. Bakaeen FG, Murr MM, Sarr MG, et al: What prognostic factors are important in duodenal adenocarcinoma? Arch Surg 135:635,2000 5. Beger HG, Treitschke F, Gansauge F, et al: Tumor of the ampulla of Vater. Arch Surg 134526, 1999 6. Bottger TC, Boddin J, Heintz A, et al: Clinicopathologic study for the assessment of resection for ampullary carcinoma. World J Surg 21:379, 1997 7. Cameron JL, Christ DW, Sitzmann JV,et al: Factors influencing survival after pancreatoduodenectomy for pancreatic cancer. Am J Surg 161:120, 1991 8. Chareton B, Coiffic J, Landen S, et a1 Diagnosis and therapy of ampullary tumors. World J Surg 20707,1996 9. Delcore R, Rodriguez FJ, Forster J, et al: Significance of lymph node metastases in patients with pancreatic cancer undergoing curative resection. Am J Surg 172:463,1996 10. Dorandeu A, Raoul JL, Siriser F, et al: Carcinoma of the ampulla of Vater: Prognostic factors after curative surgery: A series of 45 cases. Gut 40:350, 1997 11. B e r t MP, Hoffmann J, Schneider-Stock R, et al: Analysis of K-ras gene mutations in rare pancreatic and ampullary tumors. Eur J Gastroenterol Hepatol 10:1025, 1998 12. Fame11 M, Sakorafas GH, Sarr MG, et al: Villous tumors of the duodenum: Reappraisal of local vs. extended resection. Gastroenterology 116:A1310, 1999 13. Femandez-Cruz L, Johnson C, Dervenis C: Locoregional dissemination and extended lymphadenectomy in pancreatic cancer. Dig Surg 16313,1999 14. Fong Y, Blumgart LH, Lin E, et al: Outcome of treatment for distal bile duct cancer. Br J Surg 831712,1996
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