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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Periampullary carcinoma


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Halsted in 1898, was the first who attempted successfully local resection of a periampullary carcinoma, but this patient died 7 months later for a recurrent tumor. Codivilla, was the first to perform en block removal of the entire duodenum with the head of the pancreas for periampullary cancer, and Kausch, performed the first successful such resection using a twostage approach. A onestage pancreaticoduodenectomy, was described independently by Whipple and colleagues (1935) and Brunschwig (1937). Since then, some surgeons have questioned the role of resection for periampullary tumors, particularly pancreatic adenocarcinoma, based on the poor outcomes for patients after resection do not justify surgical intervention. Advances in anesthesia, surgical technique and critical care have all contributed to decline the postoperative morbidity and mortality and the benefits of resection appear to be better supported.


Periampullary carcinoma is a widely used term to define a heterogeneous group of neoplasms arising from the head of the pancreas, the distal common bile duct and the duodenum. This term should be distinguished from ampullary carcinoma as a tumor topographically centered in the region of the ampulla of Vater, which is formed by three anatomical components: the ampulla (common channel), the intraduodenal portion of the bile duct and the intraduodenal portion of the pancreatic duct. Thus, it may show intestinal and pancreatobiliary morphology. The unequivocable establishment of ampullary origin is possible in small lesions applying strict topographical criteria obtained at gross and histological examination. The presence of preinvasive (adenomas or areas of dysplasia), modification in the anatomical structures of the ampulla and the intestinal type of the carcinoma (the most frequent with strict resemblance to the adenocarcinoma of colon -rectum) can help in the distinction. Pancreatobiliary type carcinoma, the second more frequent subtype, is morphologically indistinguishable from the carcinoma of the pancreas and bile duct and usually show desmoplastic stromal reaction, whereas adenomatous areas are unfrequently found. Also, such distinction may not be possible in advanced cases, in which the only diagnosis that can be rendered is that of carcinoma of the pancreatobiliary-ampullary region. Although, the mode of presentation and treatment options for ampullary and periampullary tumors are similar, their prognosis are quite different with that for adenocarcinoma of the pancreas being much worse than for the other tumors.

The study of molecular abnormalities may help to unravel whether the ampullary carcinoma is more similar to those of the pancreas, biliary or gastrointestinal tract. The incidence of Ki-ras mutation on ampullary cancer is lower than in pancreatic carcinoma (35% vs. 90%). The overall pattern of mutation in ampullary carcinoma more closely resembles that of colorectal than pancreatic cancer. In ampullary neoplasms p53 mutations are common abnormalities associated to the transformation of adenomas/low grade cancers into morphologically high grade and clinically aggressive carcinoma. In the future, the identification of molecular abnormalities may help in discerning prognosis within cancers at the same stage.

Epidemiology, clinical characteristics and diagnosis

As a group, periampullary cancer account for >30,000 cancer related deaths per year in US. The clinical importance to differentiate ampullary cancer from those arising from periampullary structures, reside in their significant difference in the resectability and prognosis.

Ampullary cancer: It is a relatively uncommon neoplasm, which accounts for approximately 6% of periampullary malignancies with an incidence estimated at 2.9 cases for million population and accounts for approximately 0.2% of gastrointestinal tract carcinomas.

Ampullary tumors generally present at an earlier stage than periampullary tumors. Their strategic location may cause early biliary obstruction with jaundice (75%), biliary colic, bleeding or pancreatitis. Serum bilirubin and transaminase typically are elevated. This clinical presentation will often lead to an ultrasonography confirming extrahepatic biliary obstruction and to an ERCP. The latter allows direct visualization of the tumor (size and gross appearance) biliary or pancreatic duct dilatation or both. A biopsy of lesion (with snare or forceps) may differentiate between adenomas (found in up to 0.7% of the patients undergoing ERCP's in large series) and carcinomas. However sampling errors lead to unaccurate biopsy results in 15% to 40% of cases, so a biopsy diagnosis of adenoma does not rule out the presence of a deeper or remote carcinoma. Inmunnohistochemical staining for carcinoembryonic antigen may be beneficial in differentiating carcinoma from normal and adenomatous tissues. The endoscopic ultrasound (EUS) can show tumor extension into the wall of duodenum or head of the pancreas as well as lymph node involvement. The effectiveness of EUS at staging when compared with ERCP approximated 90% for the primary tumor and 75% for lymph node involvement. Also, EUS has shown higher sensitivity (93%) than magnetic resonance imaging (63%) and dynamic computed tomography (53%). However EUS cannot be expected to detect peritoneal and liver metastases.

Adenocarcinoma of the duodenum: It is a rare malignancy, it was found at only 0.035% of almost 500,000 autopsies and represents only 0.35% of all cancers of digestive tract. Despite accounting for less than 10% of the total length of the small intestine, the duodenum (most frequently the second portion) is the site of 25% to 45% of all small bowel cancers. Of the periampullary neoplasm, duodenal cancer is the least common. Nearly all are mucin-producing adenocarcinoma and may be ulcerative or polypoid. Although the disease may present in younger patients most patients are typically within the 6th to 8th decade of life and it displays no particular gender predominance. The most common presenting signs and symptoms are abdominal pain (50%), iron-deficiency anemia (40%), weightloss (40%), nausea and vomiting (30%) and obstructive jaundice (20%). The mainstay of diagnosis is either upper gastrointestinal tract radiographs (detecting approximately 90% of such lesions) and endoscopy. Computed tomography and EUS should be employed in determining tumor stage and should enable differentiation of primary duodenal carcinoma from the other periampullary tumors invading into duodenum such as pancreatic carcinoma and from others tumors such as primary duodenal lymphoma, sarcoma or carcinoid lesions.

Carcinoma of the distal bile duct: Cholangiocarcinoma is a rare malignancy of the biliary tract occurring in 27% in the distal bile duct, however the hepatic bifurcation is the most frequent involved site (60–80% of the cases). The most common presenting symptoms are jaundice (90%), abdominal pain and weightloss. Among pathological characteristics, the diameter is usually 2 cm and sclerotic adenocarcinoma moderately differentiated occurred in the majority of the patients. The combination of ultrasonography and ERCP usually makes the diagnosis.

Carcinoma of the pancreas: The incidence still seems to increase and is the fourth most common cause of cancer death in the USA, surpassed only by lung, colorectal and breast cancers. Currently, yearly 10–15 per 100,000 persons suffer from the disease in Europe and are estimated 25,000 new cases occur each year in the United States. Symptomatology is often vague and most patients present with advance disease with precludes potentially curative therapy. (For further information, see section on Pancreatic cancer).

Prognostic Factors

At the analysis of the survival after pancreatoduodenectomy patients with duodenal cancer have the longest survival at five years, from 22% to 53% when compared with other periampullary tumors. The majority of clinical studies failed to demonstrate prognostic significance for demographic factors or tumor grade. However, resection with negative resection margins found in more than 90% of patients, significantly favored survival. The influence of positive lymph nodes, occurring in 50% to 65% of patients, on survival is controversial. Several authors have demonstrated poor prognosis associated with positive nodal status. Conversely, multiples studies have shown that long survival can still be achieved with node positive tumors supporting an aggressive approach regarding resection of these tumors.

Five-years survival is also favorable in patients with ampullary carcinoma, ranging from 34% to 45%, but recent studies have reported as high as 50%. Factors universally accepted affecting favorably survival were negative resection margins, found in more than 95% of patients, and negative lymph nodes, encountered in 55% of patients. It is controversial whether intraoperative blood transfusion and the degree of tumor differentiation are important.

The 5 year-survival for patients with distal cholangiocarcinoma is 24%. Factor associated with prolonged survival are negative lymph nodes, found in only 30% of patients and well or moderate tumor differentiation occurring in 60% of resected tumors. Also, it has been noted that 29% of patients have invasion of extrapancreatic nerve plexus in contrast with only 3% in ampullary carcinoma.

The prognosis of pancreatic adenocarcinoma is one of the most dismal of all cancers, approximately 95% of all patients diagnosed with pancreatic cancer will die within one year. After potentially curative resection the 5 year survival is 5% to 20% making the worst survival of periampullary cancers. Examination of tumor spread reveal a high incidence of nodal involvement (75% of patients) and extrapancreatic plexus invasion found in 60% of patients. After resection, numerous factors have been reported to improve outcome, including tumor size < 2 cm, negative lymph nodes, negative resection margins, diploid tumor DNA content, and a lesser degree of genetic alteration. The influence of combined-modality chemotherapy and radiation therapy is still opened for clinical analysis.

One problem encountered in patients with periampullary cancers after pancreatoduodenectomy is to confirm the site of origin of these tumors. At the University of Chicago and at the Mayo Clinic, after reviewing their 3-year survivors with presumed ductal carcinoma of the pancreas, investigators found that between 29% and 39% of tumors could not be confirmed to have arisen in the pancreas. Therefore misclassification of tumors is not uncommon and should alert the pathologist that the final diagnosis is of great importance on the outcome of survival analysis after pancreatoduodenectomy.

In conclusion, in ampullary and periampullary tumors resection margin status, resected lymph node status and degree of tumor differentiation significantly influence outcome. Five year survival is most favorable for patients with duodenal cancer, followed in declining order by ampullary tumor, distal bile tumor and pancreatic adenocarcinoma.


Accurate staging is important for selecting patients with ampullary and periampullary carcinoma in whom it may be appropriate to attempt pancreatoduodenectomy with curative intent. The preoperative assessment should include investigations that are sensitive in detecting localized and potentially curable lesion and at the same time, specific enough to identify factors that render the tumor unresectable. The possibilities of endoscopic or percutaneous transtumoral stenting justifies appropriate patient selection so as to avoid needless laparotomies in those with unresectable lesions. The role of different methods of diagnosis for staging is to give information on:


Tumor size and location


The presence or abscence of hepatic peritoneal metastasis or ascites


Presence of extrahepatic tumor extension


Presence or abscence of lymph nodes particularly peripancreatic, periportal or celiac


Vascular encasement.

However, the periampullary region is difficult area to evaluate radiologically because its anatomic location within the retroperitoneum and its relationship with adjacent viscera and major vascular structures. The imaging modalities such ultrasonography, computed tomography (CT), magnetic resonance imaging and selective visceral angiography have been recognized not always be sufficiently accurate in staging periampullary tumors, even when used in combination. The use of laparoscopy (Lap) allows a detail view of the peritoneal cavity to detect tiny peritoneal tumors deposits and liver metastasis. The combination of laparoscopic-ultrasonography (LapUs) makes also possible to demonstrate the signs of local tumor invasion, peripancreatic lymphadenopathy and vascular invasion. However, this procedure is invasive and needs a general anesthesia. Recently, EUS and helical or spiral CT have opened up new horizons for the detection of small periampullary tumors, metastatic lymph node disease and metastatic involvement of the liver. The remaining limitation of these techniques include the detection of small lymph node metastases and peritoneal implants.

In conclusion, the combination of helical CT, EUS and laparoscopy or other combination such helical CT and laparoscopic-ultrasonography are cost-effective, accurate and safe means of staging periampullary tumors, which can prevent needless operation in some patients while offering potentially curative surgery for patients who would benefit. The diagnosis of cases of unsuspected metastases after Lap or LapUs may lead to either abandonment of the operation and the realization of an endoscopic stenting or to a laparoscopic bypass procedure under the same anesthetic.


For periampullary malignancies, resection offers the only hope for long term survival and without resection of the tumor the disease is uniformly fatal. Pancreaticoduodenectomy (PD) with or without (Wipple operation) pylorus preservation is the procedure of choice for these malignant tumors. Pylorus-preserving PD offers technical advantages (ease and speed) and may provide better quality of life and may prevent the occurrence of post-gastrectomy syndromes. PD consists of en block removal of the head of the pancreas, duodenum, the regional lymph nodes and the gallbladder with the distal part of the common bile duct. Local excision should only be attempted in patients with small adenocarcinoma of the ampulla of Vater who are unfit for or who refuse radical resection. In these subgroup of patients a 5year survival rate of 40% has been reported. Annual endoscopy for follow-up after local resection is mandatory to detect recurrence and offers the best chance of curative treatment.

The resectability rate is high for patients with distal cholangiocarcinoma (90%) and ampullary carcinoma (80%), but it is disappointingly low for those with pancreatic carcinoma (20%). At the time of resection, the surgeon should keep in mind that one of the histologic prognostic factors for survival was involvement of the resection margins. The rate of resection of free margins is higher (90–95%) for patients with ampullary carcinoma, duodenal cancer and distal bile duct carcinoma than those with pancreatic carcinoma (70%). Large tumor size and the presence of positive nodes should not preclude resection if it can be performed with negative resection margins. The mortality rate after PD, has decreased drastically during the past decade and is currently 0–5% in centers with experience, meaning a hospital volume of more than 25 procedures per year. PD is still associated with high rate of postoperative complications (up 50%). The most frequent complication are postoperative infections and sepsis which is thought to be related with obstructive jaundice being present in most patients prior to surgery. Some surgeons have postulated that preoperative biliary drainage would reduce postoperative morbidity and mortality. However, prospective randomized studies have failed to demonstrate an obvious advantage of preoperative biliary drainage and underlined the possible complications of this approach (bleeding, biliary leak) and its increased costs.

Therefore jaundice per se does not contribute substantially to an undesirable outcome and in the great majority of patients there is no need to resolve jaundice before the operation. However patients, with extremely high levels of bilirubin (> 30 mg/dl) who develop cholangitis, severe coagulopathy and signs of hepato-renal syndrome may be adequately prepared for the operation with either an internal or an external drainage. Biliary decompression should also be offered to a subgroup of patients with suspected metastatic disease and can result in the permanent palliation of the biliary obstruction when metastasis are confirmed.

Adjuvant Therapy

At present, postoperative adjuvant radiation therapy with and without concomitant chemotherapy does not improve longterm survival. Therefore, the combination of aggressive, but safe surgery and new agents or strategies to deliver adjuvant therapy will be needed to improve survival.


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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6924


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