Ampullary Carcinoma

Updated: Aug 24, 2022
Author: Ayana Allard-Picou, MD, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS 


Practice Essentials

Ampullary carcinoma is a rare malignant tumor originating at the ampulla of Vater, in the last centimeter of the common bile duct, where it passes through the wall of the duodenum and ampullary papilla (see the image below). Most are adenocarcinomas.[1] Patients typically present with symptoms related to biliary obstruction. A high index of suspicion is paramount so that the appropriate laboratory and imaging studies may be obtained to facilitate early diagnosis.

Endoscopic view of an ampullary carcinoma. Endoscopic view of an ampullary carcinoma.

Over the last decade, advances in technology have allowed improvements in the diagnosis and staging of this disease. Current imaging techniques enable more accurate staging of these tumors and permit preoperative determination of which tumors are surgically resectable.

Surgical resection with pancreaticoduodenectomy (the Whipple procedure) remains the gold standard for treatment, although local excision is an option for patients who may be unable to tolerate this. Several palliative options exist for patients with unresectable or metastatic disease. While certain features (eg, positive resection margins and lymph node positivity) portend poorer prognosis, patients with ampullary cancer generally have better overall survival than patients with pancreatic cancer.

Signs and symptoms

The signs and symptoms of ampullary carcinoma are largely related to obstruction of the bile duct or pancreatic duct. They include the following[2] :

  • Jaundice secondary to biliary obstruction—most common clinical presentation
  • Abdominal pain
  • Dyspepsia
  • Malaise
  • Fever/chills
  • Anorexia
  • Pancreatitis—May be the first clinical manifestation, due to obstruction of the pancreatic duct
  • Pruritus—Secondary to biliary obstruction
  • Nausea
  • Vomiting
  • Weight loss
  • Diarrhea
  • Upper GI bleed & heme positive stools—May occur due to ulceration of ampullary mass (less common)
  • Courvoisier gallbladder (ie, a distended, palpable gallbladder in a patient with jaundice)

See Presentation for more detail.


Laboratory studies

Routine laboratory studies include the following:

  • Complete blood count

  • Electrolyte panel

  • Liver function studies: Prothrombin time, bilirubin (direct and indirect), transaminases, and alkaline phosphatase

  • CA 19-9: Serum tumor marker that is often elevated in pancreatic malignancies and may have a role in assessing response to therapy and/or predicting tumor recurrence

  • Carcinoembryonic antigen (CEA): A nonspecific tumor marker that is sometimes elevated in pancreatic malignancies; it may have a role in assessing response to treatment or predicting tumor recurrence

Ultrasonography of the abdomen

  • Abdominal ultrasonography is the initial study to evaluate the common bile duct or pancreatic ducts

  • Dilatation of these ducts is essentially diagnostic for extrahepatic biliary obstruction

  • Biliary or pancreatic ductal dilatation can explain abdominal pain, even in patients with localized and noninvasive disease

  • 10-15% of patients with normal common bile duct findings on ultrasonography demonstrate extrahepatic biliary obstruction on a computed tomography (CT) scan

  • Ultrasonography and CT scanning can help reveal metastatic disease in the liver or regional lymph nodes

CT scanning of the abdomen and/or pelvis

  • Obtain a CT scan to evaluate the local region of interest and evaluate for possible metastases

  • CT scanning often demonstrates a mass but is not helpful in differentiating ampullary carcinoma from tumors of the head of the pancreas or periampullary region; if the lesion is smaller than 2 cm, pancreatic or bile duct dilation may be the only abnormalities noted on the CT scan

  • Such findings are highly suggestive of pancreatic malignancy and require further evaluation, usually with endoscopic retrograde cholangiopancreatography (ERCP)

  • Dynamic CT scanning (ie, high-speed scans obtained during rapid intravenous administration of iodinated contrast material) can reveal tumor involvement of the vasculature

Other imaging studies

  • ERCP: Obtain ERCP to evaluate the ductal architecture further

  • Chest radiography: Obtain a chest radiograph to complete the workup (ie, for staging purposes)

  • Positron emission tomography (PET) or PET-CT scanning: PET or PET-CT scans can detect metastases that are too small to be reliably detected on a CT scan

See Workup for more detail.


The standard surgical approach to the treatment of ampullary carcinoma is pancreaticoduodenal resection (Whipple procedure). The procedure traditionally involves en bloc resection of the gastric antrum and duodenum; a segment of the first portion of the jejunum, gallbladder, and distal common bile duct; the head and often the neck of the pancreas; and adjacent regional lymph nodes.

The operative mortality rate for pancreaticoduodenectomy was at one time reported to be approximately 20%, but several hospital centers have since reported large series with operative mortality rates in the range of 5%.

See Treatment for more detail.


Carcinoma of the ampulla of Vater is a malignant tumor arising in the last centimeter of the common bile duct, where it passes through the wall of the duodenum and ampullary papilla. The pancreatic duct (of Wirsung) and common bile duct merge and exit by way of the ampulla into the duodenum. The ductal epithelium in these areas is columnar and resembles that of the lower common bile duct.

Adenocarcinoma of the ampulla of Vater is relatively uncommon, accounting for approximately 0.2% of gastrointestinal tract malignancies and approximately 7% of all periampullary carcinomas.


The periampullary region is anatomically complex, representing the junction of 3 different epithelia, pancreatic ducts, bile ducts, and duodenal mucosa. Grossly, carcinomas originating in the ampulla of Vater can arise from 1 of 4 epithelial types:

  • Terminal common bile duct
  • Duodenal mucosa
  • Pancreatic duct
  • Ampulla of Vater

Distinguishing between true ampullary cancers and periampullary tumors is critical to understanding the biology of these lesions. Each type of mucosa produces a different pattern of mucus secretion. In a complete histochemical study, Dawson and Connolly divided acid mucins into sulphomucins and sialomucins; in general, ampullary cancers produce sialomucins, whereas periampullary tumors secrete sulfated mucins. These researchers demonstrated that ampullary tumors secreting sialomucins had a better prognosis (100% vs 27% 5-year survival rate).[3] Other investigators have confirmed the prognostic power of the pattern of mucin secretion.

Ampullary adenocarcinomas have two principal histologic forms: intestinal and pancreaticobiliary.[4] The intestinal form is thought to originate from the intestinal epithelium above the ampulla, while the pancreaticobiliary form is thought to originate from the epithelium of the distal pancreatic duct and the common bile duct.[5] The clinical behavior of these tumors reflects this classification; the course of intestinal ampullary adenocarcinomas is similar to that of their duodenal counterparts, whereas pancreaticobiliary tumors follow a more aggressive course, similar to that of pancreatic adenocarcinomas.[4]

However, 20-40% of ampullary adenocarcinomas are mixed types, showing both pancreaticobiliary and intestinal features.[6, 5] Proposed definitions for mixed-type ampullary carcinoma vary, with different authors suggesting that at least 10% or at least 25% of both histologic subtypes must be present, or that hematoxylin and eosin (HE) staining results should be used to guide diagnosis.[5]

In addition, poorly differentiated tumors can further confound the histological classification. The prognostic significance of this histological classification has been subjected to investigation, with inconsistent results.[7, 8]


Immunohistochemical stains for expressions of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, Ki-67, and p53 have been studied for prognostic power. In a series of 45 patients, expression of CA 19-9 labeling intensity and apical localization both were statistically significant predictors of poor prognosis. Although earlier studies suggested that CA 19-9 may be used as a prognostic marker, a study by Zhou et al did not demonstrate a difference in survival based on CA 19-9 level.[9] CEA expression also might be a marker for prognosis, but it may also be elevated in other GI malignancies. Ki-67 and p53 have not been demonstrated to have an effect on outcome. Research along these avenues ultimately might provide the rationale for discriminative administration of adjuvant therapy.



Ampullary carcinoma is a relatively uncommon tumor that accounts for approximately 0.2% of gastrointestinal tract malignancies and approximately 7% of all periampullary carcinomas in the United States.[1] A review of data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program found 6803 patients with ampullary cancer between 2004 and 2013; the annual incidence has been fairly constant since 2004.[10]

An epidemiologic study of ampullary cancer in the Netherlands found that the incidence rate increased from 0.59 per 100,000 in 1989-1995 to 0.68 per 100,000 in 2010-2016. In patients with non-metastatic ampullary isease, five-year overall survival increased from 19.8% in 1989-1995 to 29.1% in 2010-2016.[11]


Pancreaticoduodenectomy is a formidable operation, and the morbidity and mortality rates associated with this procedure historically have been high.

Until recently, the operative mortality rate was reported to be approximately 20%. In the past few years, several centers have reported large series with a perioperative mortality rate in the range of 5%. In a 2008 population-based analysis of 1301 ampullary cancer patients who underwent resection, perioperative mortality was 7.6% and 5-year survival was 37%.[12] A review of the last 130 pancreaticoduodenectomies performed at Stanford University Medical Center over the previous 5 years revealed an operative mortality rate of 3%. This improvement can be attributed to increased surgical experience, improved patient selection, improved anesthesia, better preoperative imaging, and general improvement in the management of ill patients.

The morbidity rate associated with the surgery is approximately 65%. In some series, 13% of patients required a repeat laparotomy for complications. Patients may experience fistula formation, delayed intestinal function, pneumonitis, intra-abdominal infection, abscess, or thrombophlebitis. Marginal ulceration, diabetes, pancreatic dysfunction (steatorrhea), and gastrointestinal motility disorder all can manifest as late complications of the surgery.

Race- and sex-related demographics

Because ampullary carcinoma is relatively uncommon, studies of the patterns of occurrence among different ethnic groups have not been conducted.

Ampullary cancer is more common in men, according to the SEER program.[10, 13]


Reviews of single-institution surgical experiences of ampullary cancer have focused on the identification of histopathologic features associated with prognosis and survival. Retrospective review, small patient numbers, and long periods of enrollment limit what can be learned from these studies. However, common themes emerge from these published clinicopathologic analyses.[14]

Survival after surgical resection is related to the extent of local invasion of the primary lesion, lymph node involvement, vascular invasion, perineural invasion, cellular differentiation, and uninvolved surgical margins. Even a single lymph node with evidence of metastatic carcinoma portends a poor outcome with surgery alone. Exactly which factors are truly independent remains controversial.

El-Ghazzawy et al reviewed experiences in the US Department of Veterans Affairs hospitals from 1987-1991, during which time 123 patients were diagnosed with ampullary cancer. In the group that underwent surgical resection, perineural invasion, microlymphatic invasion, vascular invasion, or tumor differentiation did not independently influence survival when the tumors were controlled for stage.[15]

A review of 5625 cases from the SEER database noted that patients with high-grade tumors demonstrated worse overall survival than those with lowergrade tumors.[13]

In a retrospective review by Sudo et al of 46 consecutive cases of ampullary carcinoma, multivariate analysis showed perineural invasion to be a significant independent predictor of poor prognosis (P = 0.024). On univariate analysis, other significant predictors of poor prognosis were T3 and T4 tumors (ie, pancreatic parenchymal invasion) (P < 0.001) and lymph node metastasis (P = 0.01).[16]

Multivariate analysis of 302 cases by Lowe et al also showed that perineural invasion is associated with lower survival (hazard ratio [HR] 4.62, 95% confidence interval [CI] 1.11-19.21), as was N1 disease (HR 4.50, CI 1.16-17.40).[15]

A retrospective study of 50 patients by Uchida et al found that patients with preoperative jaundice had poorer survival than those without jaundice (5-year survival 57.2% vs. 100%, respectively, P < 0.01).[17]

Similarly, Carter et al reported that patients with pancreaticobiliary ampullary adenocarcinomas, whose survival was worse than that of patients whose tumors had intestinal histology, were more likely to present with jaundice. This study also drew similarities in patterns of behavior based on histologic subtype, noting that intestinal ampullary adenocarcinomas behaved similarly to their duodenal counterparts, whereas pancreaticobiliary ampullary cancers were generally more aggressive and behaved like pancreatic adenocarcinomas.[4]

In a series and meta-analysis by Yao et al, patients with an allogeneic blood transfusion requirement of ≥3 units had poorer 3-year and 5-year survival than those transfused with 2 units or non-transfused patients (P < 0.05).[18]

 Table 1 summarizes the outcomes for patients with involved lymph nodes.

Table 1. Summary of 5-Year Survival After Resection for Lymph Node Negative and Positive Carcinoma of the Ampulla of Vater (Open Table in a new window)


Node-Negative, % (#)

Node-Positive, % (#)

P Value

University of Alabama at Birmingham[19]

78 (19)

50 (5)

Not significant

Mayo Clinic, Minnesota[20]

43 (53)

16 (50)


Montebelluna Hospital, Italy[21]

64 (22)

0 (9)


Academic Medical Center, Amsterdam[22]

59 (32)

41 (35)


Niigata University, Japan[23]

81 (17)

41 (18)

< 0.01

Johns Hopkins, Baltimore[24]

43 (53)

31 (50)


Kanazawa University Hospital, Japan[25]

74 (21)

31 (15)

< 0.05

Memorial Sloan Kettering, New York[26]

55 (55)

30 (46)


Loyola University, Chicago[27]

78 (27)

25 (24)

< 0.05

Jagiellonian University Medical College, Krakow, Poland[28]

59 (53)

52 (47)

< 0.001

University of Verona, Italy[29]

59 (46.5)

68 (53.5)

< 0.0001

In a study of 37 patients, Haruki et al reported that the preoperative neutrophil-to-lymphocyte ratio (NLR) is an independent and significant indicator of long-term outcome after pancreaticoduodenectomy for carcinoma of the ampulla of Vater. An NLR ≥3 was a significant predictor of reduced overall survival (P=0.026).[30]

Patients with ampullary tumors have an overall better prognosis than those with pancreatic cancer and studies have demonstrated better survival after surgical resection for ampullary cancer. Ampullary tumors are more likely to result in biliary obstruction earlier in their course, and therefore tend to present at an earlier stage compared to most pancreatic cancers.[2]

Allema et al reported a 5-year overall survival rate of 50% in patients who underwent resection (subtotal or total pancreaticoduodenectomy) for ampullary cancer. Additionally, This series demonstrated that involvement of resection margins was the strongest prognostic factor for overall survival: patients with negative margins at resection had 5-year survival rates of up to 60%, compared with 15% in patients with positive margins (P < 0.001).[22]

A systematic review of 71 studies (8,280 patients) by Zhou et al noted a median 5-year overall survival rate of 58% and disease-free survival rate of 51%.[31] Adjuvant therapy was associated with improved overall survival. The following factors were independently associated with worse overall survival:

  • Age > 65 years at diagnosis
  • Tumor size > 20 mm
  • Poor differentiation
  • Pancreaticobiliary histotype
  • pT3-4 stage disease
  • Lymph node metastasis
  • Number of metastatic nodes
  • Perineural invasion
  • Lymphovascular invasion
  • Vascular invasion
  • Pancreatic invasion
  • Positive surgical margins

Patterns of failure

Unfortunately, most patients with carcinoma of the ampulla of Vater die of recurrent disease. Treatment fails in nearly 70% of patients with poor prognostic features, and these patients ultimately die of their disease.

Kim and associates described a 5-year locoregional recurrence rate of 9.6% in 259 patients with ampullary cancers following potentially curative resection. Regional nodal recurrences were noted in 76 or 29.3% of the patients with recurrence.[32]




The most common clinical manifestation of ampullary carcinoma is jaundice, which occurs due to obstruction of the biliary tract by the tumor. Patients may also experience scleral icterus and pruritus because of obstruction of the bile duct. Other common complaints include dyspepsia, anorexia, malaise, and weight loss.

Pancreatitis may sometimes be the initial clinical presentation due to pancreatic duct obstruction. Patients may therefore complain of symptoms of pancreatitis, such as epigastric/mid-abdominal pain, back pain, nausea, and vomiting.

Diarrhea, a common but not universal symptom, might be associated with an absence of lipase within the gut because of pancreatic duct obstruction.

Physical Examination

Physical examination sometimes reveals a Courvoisier’s sign (ie, a distended, palpable gallbladder in a patient with jaundice). Fever can be present, particularly when the biliary tract has been explored previously (eg, after common duct exploration for stones, or after endoscopic retrograde cholangiopancreatography [ERCP]).



Diagnostic Considerations

Other conditions to consider in the differential diagnosis include duodenal adenoma, as well as the following ampullary tumors:

  • Carcinoids
  • Neuroendocrine tumors
  • Gastrointestinal stromal tumors (GISTs)
  • Lipomas
  • Adenomyomatosis


Differential Diagnoses



Approach Considerations

In the workup of ampullary carcinoma, diagnostic modalties of choice are as follows[33] :

  • Endoscopic ultrasound (EUS)
  • Endoscopic retrograde cholangiopancreatography (ERCP)
  • Fine-needle aspiration cytology (FNAC)

Staging of ampullary carcinoma requires computed tomography (CT) of the chest, abdomen, and pelvis. Endoscopic ampullectomy may be part of the diagnostic process and may be curative in highly selected cases (eg, early ampullary carcinoma, in situ carcinoma, low-grade dysplasia).[33]

Laboratory Studies

Routine laboratory studies include the following:

  • Complete blood cell count
  • Electrolyte panel
  • Liver function studies (prothrombin time, bilirubin [direct and indirect], transaminases, alkaline phosphatase)
  • Cancer antigen 19-9 (CA 19-9)
  • Carcinoembryonic antigen (CEA)

A rising bilirubin level due to obstructive jaundice often is the sole presenting sign.

CA 19-9 is a serum tumor marker that is often elevated in pancreatic malignancies and might have a role in assessing response to therapy, predicting tumor recurrence, or both.

CEA is another nonspecific tumor marker that sometimes is elevated in pancreatic malignancies. Measurement of CEA might have a role in assessing response to treatment or predicting tumor recurrence. Because CEA also is elevated in patients with other gastrointestinal malignancies (in particular, colon and rectal cancer), the possibility of a second primary tumor needs to be excluded in these patients.

Imaging Studies


Abdominal ultrasound is the initial study to evaluate the common bile duct or pancreatic ducts. Dilatation of these ducts essentially is diagnostic for extrahepatic obstruction and can explain abdominal pain, even in patients with localized and noninvasive disease. However, 10-15% of patients with normal common bile duct findings on ultrasonography demonstrate extrahepatic biliary obstruction on a computed tomography (CT) scan. Both ultrasound and CT can help reveal metastatic disease in the liver or regional lymph nodes.

Computed tomography

Obtain a CT scan image to evaluate the local region of interest (abdomen, pelvis, or both) and evaluate for possible metastases. CT scan often demonstrates a mass but is not helpful in differentiating ampullary carcinoma from tumors of the head of the pancreas or periampullary region. If the lesion is smaller than 2 cm, pancreatic or bile duct dilation might be the only abnormalities noted on CT scan. Such findings are highly suggestive of pancreatic malignancy and require further evaluation, usually with endoscopic retrograde cholangiopancreatography (ERCP).

Dynamic CT scanning (ie, high-speed scans obtained during rapid intravenous administration of iodinated contrast material) can reveal tumor involvement of the vasculature. Some centers still rely on angiography to help identify patients with potentially resectable disease.

Ampullary multidetector computed tomography (MDCT) can be useful to differentiate pancreatobiliary and intestinal subtypes of ampullary adenocarcinoma preoperatively, provided the duodenum is optimally distended at imaging.[34]

Endoscopic ultrasound

Endoscopic ultrasound (EUS) is often used as a part of the local staging. EUS allows visualization of the duodenal wall, ampulla, bile duct, and pancreatic duct, as well as regional lymph nodes. EUS can facilitate biopsy of the tumor via fine needle aspiration (FNA) and is also used to evaluate regional lymph nodes for lymph node metastasis. Lastly, EUS allows visualization of celiac and superior mesenteric vessels to evaluate for vascular invasion.

In one series comparing the accuracy of EUS and CT for staging of ampullary cancer, EUS demonstrated a better sensitivity, specificity, positive predictive value, and negative predictive value stage for stage.[35]

Intraductal ultrasonography has been reported by some to more accurately visualize tumor infiltration into the duodenal wall and ampulla.

Endoscopic retrograde cholangiopancreatography

Obtain ERCP to evaluate the ductal architecture further. The following findings on ERCP suggest pancreatic cancer:

  • Irregular pancreatic duct narrowing
  • Displacement of the main pancreatic duct
  • Destruction or displacement of the side branches of the duct
  • Pooling of contrast material in necrotic areas of tumor

Chest radiograph

Obtain a chest x-ray film to complete the workup (ie, for staging purposes).

Positron emission tomography

Positron emission tomography (PET) or PET-CT scans have been widely adopted in the author's clinic as a means of imaging the metabolic activity of a particular tumor. PET or PET-CT scans can detect metastases that are too small to be reliably detected on a CT scan.


Over the years, multiple systems for staging this tumor have been proposed. Martin proposed a 4-stage system, as follows:

  • Stage I - Vegetating tumor limited to the epithelium with no involvement of the sphincter of Oddi

  • Stage II - Tumor localized in the duodenal submucosa without involvement of the duodenal muscularis propria but possible involvement of the sphincter of Oddi

  • Stage III - Tumor of the duodenal muscularis propria

  • Stage IV - Tumor of the periduodenal area or pancreas, with proximal or distal lymph node involvement

The classification system of Yamaguchi and Enjoji is similar to the Martin classification.[36]

Talbot et al devised a system that scored tumors according to the degree of infiltration (from 1-4 according to increasing infiltration) and according to tumor differentiation (from 1-3 for well, moderately, and poorly differentiated tumors), the sum of which separated the patients into 2 groups (scores 2-4 and scores 5-7).[37]

The currently accepted American Joint Committee on Cancer staging system (8th edition) for ampullary carcinoma emphasizes the importance of pancreatic invasion and lymph node metastases (see below and see Table 1, below). Size has little impact on tumor stage. The definition of primary tumor (T), regional lymph node (N), and remote metastases (M) for classification and staging of cancer of the ampulla of Vater is provided below.[38]

Primary tumor is defined as follows[38] :

  • TX – Primary tumor cannot be assessed
  • T0 – No evidence of primary tumor
  • Tis – Carcinoma in situ
  • T1a – Tumor limited to ampulla of Vater or sphincter of Oddi
  • T1b – Tumor invades beyond the sphincter of Oddi (perisphincteric invasion) and/or into the duodenal submucosa
  • T2 – Tumor invades duodenal wal
  • T3a – Tumor invades pancreas (up to 0.5 cm)
  • T3b – Tumor extends more than 0.5 cm into the pancreas, or extends into peripancreatic tissue or duodenal serosa without involvement of the celiac axis or superior mesenteric artery
  • T4 – Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, irrespective of size

Regional lymph nodes are defined as follows:

  • NX – Regional lymph nodes cannot be assessed
  • N0 – No regional lymph node metastases
  • N1 – Metastasis to one to three regional lymph nodes
  • N2 – Metastasis to four or more regional lymph nodes

Distant metastases are defined as follows:

  • MX – Presence of distant metastases cannot be assessed
  • M0 – No distant metastases
  • M1 – Distant metastases

Table 2. Staging of Ampullary Cancers by the TNM System. [38] (Open Table in a new window)





Stage 0




Stage I




Stage IB




Stage IIA




Stage IIB




Stage IIIA




Stage IIIB


Any T

Any N




Stage IV

Any T

Any N





Surgical Care

The standard surgical approach is pancreaticoduodenal resection (Whipple procedure). The procedure involves en bloc resection of the following:

  • The gastric antrum and duodenum
  • A segment of the first portion of the jejunum, gallbladder, and distal common bile duct
  • The head and often the neck of the pancreas
  • Adjacent regional lymph nodes

In a review of 450 cases of surgical resection of ampullary adenoma or adenocarcinoma at Johns Hopkins, Winter et al found that 96.7% of the patients had undergone pancreaticoduodenectomy rather than local excision. These researchers concluded that pancreaticoduodenectomy should be the preferred approach for most ampullary neoplasms that require surgical resection, given that nearly 30% of the Johns Hopkins patients with T1 disease had lymph node metastases.[39]

Factors associated with the presence of lymph node metastasis included the following[39, 40] :

  • Tumor size ≥1 cm (odds ratio [OR] 2.1)
  • Poor histologic grade (OR 4.8)
  • Perineural invasion (OR 3.0)
  • Microscopic vessel invasion (OR 6.6)
  • Depth of invasion > pT1 (OR 4.3; all P < 0.05)
  • Specifically, risk of lymph node metastasis increased with T stage (T1, 28.0%; T2, 50.9%; T3, 71.7%; T4, 77.3%; P < 0.001)

Results after radical resection of ampullary of Vater carcinoma have been improving. During recent decades, 5-year survival rates have ranged from 20-61%, averaging higher than 35%. The reported mortality rates from this operation are decreasing. A summary follows in Table 3, below.

Table 3. Results of Pancreaticoduodenal Resection for Carcinoma of the Ampulla of Vater (Open Table in a new window)



Patients, #

Resected, #

Mortality Rate, %

5-Year Survival Rate, %

Cleveland Clinic[41]






Leicester Royal Infirmary, United Kingdom[42]






University of Alabama[17]






Mayo Clinic[18]






Montebelluna Hospital, Italy[21]






Veterans Affairs hospitals[12]






Academic Medical Center, The Netherlands[19]






Hanover Hospital, Germany[43]






Johns Hopkins[16]






Johns Hopkins[44]






Memorial Sloan Kettering[26]






Catholic University, Italy[45]






General National Hospital, Indonesia







In a review of more than 1100 patients published in a surgical series, Howe et al reported that the overall rate of resectability was 82%.[26] This most likely overestimates the true resectability rate because patients in whom radiologic studies identify unresectable disease often are not included in retrospective surgical series.

A review of cases from Veterans Affairs hospitals across the United States by el-Ghazzawy et al revealed that only 63% of presenting patients undergo surgery for cure. At disease presentation, 30-50% have involved lymph nodes.[15]

A few studies have been conducted on the pattern of lymphatic spread of ampullary cancer. These studies have been difficult to interpret because of the lack of standardized nomenclature for lymph node groups, variability in the degree of superior mesenteric lymph node dissection, and the small number of patients.

Shirai and colleagues meticulously reviewed 21 cases of ampullary cancer and documented the pattern of lymphatic spread. The site of greatest nodal involvement, the first echelon group, is the posterior pancreaticoduodenal nodal group. The nodal groups surrounding the inferior pancreaticoduodenal artery were the superior mesenteric lymph nodes involved most often. Finally, the para-aortic lymph node groups were involved in 3 patients with resectable disease.[23]

Kayahara reported that the inferior pancreaticoduodenal nodes (13b) and the superior mesenteric nodes (14) were the groups most often involved with metastatic carcinoma.[25]

Whipple procedure

Preoperative details include the following:

  • Assessment of nutritional status and supplementation when necessary (fortunately, most of these patients do not have any nutritional problems).

  • Standard mechanical and oral antibiotic bowel preparation may be considered, but it is not essential for pancreaticoduodenectomy.

  • Assessment of coagulation profile and correction of decreased prothrombin time by administration of vitamin K in patients with advanced jaundice

  • Intravenous antibiotic prophylaxis

  • Preoperative biliary drainage in jaundiced patients is indicated in patients with cholangitis and those with profound hyperbilirubinemia as this may impact coagulation status and wound healing. Preoperative stenting may be associated with increased postoperative infectious complications.

  • Fluid and electrolyte correction

  • Assessment of cardiac, renal, and pulmonary status

Intraoperative details include the following:

  • Laparoscopic assessment is obtained for peritoneal metastasis; hepatic metastases; and extensive lymphatic, vascular, or surrounding organ invasion.

  • Resectability of the primary tumor is determined by mobilizing the head of the pancreas (ie, Kocher maneuver), opening the lesser sac, and exposing and inspecting the confluence of the splenic vein and superior mesenteric vein. Involvement of the retropancreatic portal vein is not a universal contraindication, as this segment of portal vein may be resected en bloc and subsequent reconstruction of the vein performed (this is shown in the image below).

    Kocherization of the duodenum. For ampullary malig Kocherization of the duodenum. For ampullary malignancies greater than 1 cm in size, pancreaticoduodenectomy is the preferred operation. This figure demonstrates the process of kocherization of the duodenum. The second and third portions of the duodenum are mobilized en bloc with the periduodenal nodal tissue. The authors prefer to expose the inferior vena cava (IVC) and remove alveolar tissue, which lies above the IVC en bloc with the specimen.
  • Intraoperatively, a transduodenal fine needle aspiration or core biopsy is the preferred method for pathologic confirmation of the diagnosis. In about 10% of cases, these methods do not permit intraoperative confirmation of carcinoma. Resection should be performed in such cases based on preoperative and intraoperative findings.
  • Resectability may be a subjective determination based on the experience and skill of the surgeon.
  • Insertion of a feeding jejunostomy or nasojejunal tube during the procedure may be considered, to permit early resumption of enteral feeding; however, this is rarely necessary.
  • The pancreas is transected anterior to the portal vein to resect the pancreatic head and uncinate process with the specimen. The duodenum and gastric antrum are resected with the pancreatic head in the classic Whipple procedure. The gallbladder and distal bile duct are also resected. Peripancreatic lymph nodes are included with the resection.
  • Intraoperative frozen section of the bile duct and pancreatic margins are confirmed negative prior to reconstruction.
  • Restoration of gastrointestinal continuity is completed with pancreaticojejunostomy or pancreaticogastrostomy, hepaticojejunostomy, and gastrojejunostomy (these are depicted in the illustration below).
    Ampullary carcinoma. Roux-en-Y reconstruction foll Ampullary carcinoma. Roux-en-Y reconstruction following completion of a standard pancreaticoduodenectomy.

Local excision

In general, for ampullary carcinoma, pancreaticoduodenectomy remains the gold standard and should be offered as long as the patient is able to tolerate the operation.[2] However, because of the mortality and morbidity associated with pancreaticoduodenectomy, surgeons have studied local excision of cancers of the ampulla of Vater to avoid major resection. Transduodenal excision of ampullary tumors has been proposed as an intermediate option between radical resection and palliative bypass for high-risk patients. However, this approach remains highly controversial.

Local resection has generally been reserved for poor operative candidates (eg, elderly patients, those with other comorbid conditions) with favorable tumors (generally < 2 cm, polypoid). Unfortunately, this approach compromises local control and has a higher risk of a positive margin, possibly requiring repeat excisions and resulting in higher local recurrence rates of up to 30%.[46] Additionally, lymph node metastasis may be present even in patients with T1 tumors and local resection does not include a regional lymphadenectomy, as is performed with pancreaticoduodenectomy.

Some have argued that local resection is simpler, is better tolerated and may have acceptable survival rates. In a series of 21 patients who underwent local resection of ampullary adenomas, Posner et al demonstrated overall survival of 85% and no tumor recurrence in 89% of the surviving patients (with average follow up of 38 months). However, this study was not limited to ampullary cancer; final pathology demonstrated 1 patient (5%) with invasive cancer, 2 (9%) with microinvasive cancer, 6 (28%) with high-grade dysplasia, and 1 (5%) with low-grade dysplasia.[47]

Carcinoma in situ has been diagnosed with increasing frequency. It has been associated with polypoid growth and may be treated with endoscopic polypectomy. In these circumstances, the entire polyp should be removed and the base of the polyp should be carefully examined to ensure that no cancer is at the margin. In the case of an incomplete excision, a prompt pancreaticoduodenectomy is essential. Patients who undergo polypectomy only should be monitored endoscopically at yearly intervals to detect any recurrence.

Staging of ampullary cancer is critical to treatment. While ampullary polypectomy and ampullectomy have been performed successfully on some patients with ampullary cancer, local resection as a therapeutic approach is best reserved for patients with benign lesions, such as ampullary adenomas, or patients with carcinoma in situ or T1 tumors whose overall performance status makes the risks associated with a formal pancreaticoduodenectomy excessive.

Yamamoto et al reported successful use of endoscopic papillectomy to treat 27 patients with Tis-T1a ampullary carcinoma. Mean tumor size was 14.1 mm. On median follow-up of 48.5 months, no patient experienced recurrence of disease.[48] Shimai et al reported that endoscopic papillectomycan be curative in patients with small ampullary neuroendocrine tumors that have been preoperatively diagnosed as located within the submucosal layer and that show no evidence of lymphovascular invasion or lymph node metastasis.[49]

A study by Kohga et al that included 25 patients with pathological T1 (pT1) ampullary carcinoma concluded that local resection may be considered in selected patients who are preoperatively diagnosed with T1a ampullary carcinoma.[50] Lymph node metastasis did not develop in any of the four patients who met the following criteria for local resection:

  • Tumor limited to the mucosa
  • No apparent lymph node metastasis or distant metastasis
  • Tumor small enough to permit complete removal with local resection

For patients with clinical T1b ampullary carcinoma, these authors recommend considering pancreaticoduodenectomy with lymph node dissection.[50]

Palliative surgery

Palliative surgery is reserved for patients who have unresectable tumors but who are good candidates for surgery. The goal is to alleviate biliary obstruction, duodenal obstruction, or pain. Either cholecystojejunostomy or hepaticojejunostomy bypass is performed. Duodenal obstruction may require gastrojejunostomy.[51] A review by Gurusamy et al concluded that patients with unresectable periampullary cancer should undergo gastrojejunostomy even if the duodenum is unobstructed at the time of laparotomy, because as many as one third of patients develop obstruction later. However, prophylactic gastrojejunostomy poses significant morbidity risk.[51]

Chemical splanchnicectomy, using either 6% phenol or 50% ethanol, can be performed intraoperatively. This procedure controls pain in 80% of patients.

Adjuvant Therapy

Because local and systemic failures remain problematic, physicians continue to be interested in offering adjuvant therapy. The relative rarity of this disease limits research in this area.[52, 53] However, a systematic review and meta-analysis of 27 studies involving 3,538 patients concluded that adjuvant therapy was significantly associated with decreased mortality risk (hazard ratio [HR], 0.58; 95% confidence interval [CI] 0.40-0.84), especially for chemoradiotherapy (HR, 0.42; 95% CI, 0.28-0.62). Adjuvant therapy was significantly associated with increased overall survival in high-risk patients (HR, 0.63; 95% CI, 0.48-0.82) and patients with the pancreaticobiliary subtype (HR, 0.53; 95% CI, 0.32-0.85), but not in low-risk patients (HR, 0.93; 95% CI, 0.52-1.68) or those with the intestinal subtype (HR, 1.06; 95% CI, 0.57-1.95).[54]

Willett and colleagues summarized their experience with adjuvant radiotherapy for high-risk tumors of the ampulla of Vater (risk factors included invasion into the pancreas, poorly differentiated histology, involved lymph nodes, or positive resection margins).[55] Twelve patients received adjuvant radiotherapy (40-50.4 Gy) to the tumor bed and some received concurrent 5-fluorouracil (5-FU) as a radiosensitizer. Comparison of these patients with 17 patients who underwent surgical resection alone showed a trend toward better locoregional control with adjuvant radiotherapy, but there was no advantage in survival. Distant metastasis to the liver, peritoneum, and pleura was the dominant failure pattern in this group of patients.

Nassour and colleagues reviewed the National Cancer Database for patients who underwent resection between 2004-2013 and received adjuvant chemotherapy or adjuvant chemoradiotherapy. Of 4,190 patients, 21% received adjuvant chemotherapy and 16% underwent adjuvant chemoradiotherapy. Receipt of adjuvant chemotherapy or chemoradiotherapy was associated with improved overall survival (hazard ratio [HR] = 0.82, and HR = 0.84, respectively).[56]

The Johns Hopkins Hospital and the Mayo Clinic collaborated on a study of adjuvant therapy in patients who underwent curative surgery for ampullary carcinoma at their institutions from 1977 to 2005. Of 186 patients, 120 received surgery alone while 66 were given adjuvant chemoradiotherapy (5-FU–based chemoradiation with a total of 45 Gy delivered to the ampullary tumor bed, surgical anastomoses, and adjacent regional lymph nodes, with an additional 5-15 Gy delivered to the involved margins and anastomoses; 38% received maintenance chemotherapy, with 15% receiving single-agent 5-FU and 19% receiving single-agent gemcitabine). Adjuvant chemoradiation treatment was not significantly associated with overall survival when compared with surgery alone (median survival 39.9 vs. 40.1 months, RR 0.64 - 1.43, P = 0.839), except in patients with pathologic lymph node involvement (median survival 32.1 vs. 15.7 months, P = 0.004).[57]

Sikora and colleagues presented their experience from a hospital in India in a retrospective review. Patients who underwent a pancreaticoduodenectomy with adjuvant chemotherapy and radiation did not do any better than the group treated with surgery alone.[58]

Zhou et al reviewed the records of 111 patients at Johns Hopkins who underwent curative surgery for ampullary adenocarcinoma, 45% of whom also received adjuvant chemotherapy and radiation. In these patients, the improvement in survival with adjuvant treatment was not statistically significant (median overall survival: 21.6 vs. 13.0 months, P=0.092).[59]

A Mayo Clinic study found that in patients with advanced ampullary cancer, defined as stage IIIB or higher, adjuvant therapy was independently associated with improved disease-free survival (hazard ratio [HR] 0.52, P = 0.04) and overall survival (HR 0.45, P = 0.03). In this study, of 121 consecutive patients treated from 2006 to 2016, 53 patients underwent adjuvant therapy after pancreaticoduodenectomy, with 34 patients receiving chemotherapy alone (most commonly single-agent gemcitabine, although FOLFOX was administered in 3 patients and FOLFIRINOX administered in 1 patient) and 19 patients receiving chemoradiation therapy (most commonly gemcitabine alone for 3 cycles followed by gemcitabine (or capecitabine) given concurrently with radiation followed by gemcitabine for another 3 cycles).[60]

At Stanford University, all cases of periampullary carcinoma are discussed and reviewed in detail by a multidisciplinary team that includes surgical oncologists, medical oncologists, radiation oncologists, a pathologist, a gastroenterologist, and a radiologist. All resected tumors are reviewed. Patients with tumors with poor prognostic features (eg, involved surgical margins, lymph nodes, invasion of the pancreas, perineural invasion, or poor histologic grade) are enrolled in a single-arm investigational protocol to receive adjuvant radiotherapy (45 Gy) and concurrent protracted venous infusion of 5-FU (225 mg/m2/d) during the entire treatment course.

Patients with carcinoma of the ampulla of Vater may benefit from recent advances in the treatment planning and delivery of adjuvant and definitive radiotherapy for patients with pancreatic cancer, which have produced modest gains in survival.

Pancreaticoduodenectomy is the procedure of choice for patients with resectable disease, but local recurrence plagues all surgical series, particularly when the pancreas has been invaded or lymph node metastases are discovered. In fact, whether major resection impacts survival in the setting of disease spread to the lymph nodes remains unclear. Postoperative irradiation of at least 45 Gy with 5-FU as a radiosensitizer is a reasonable treatment and reduces local recurrence in pancreatic cancer.

Treatment of Unresectable Disease

For patients with unresectable ampllary carcinoma, endoscopic stenting to achieve biliary decompression is an appropriate palliative procedure. Endoscopic palliation may also be performed for duodenal obstruction with expandable metal stents. Similarly, a palliative bypass may be performed for tumors found to be unresectable intraoperatively.

No established answer exists to the question of further therapy. Data on adjuvant treatment for locally advanced and advanced ampullary carcinoma are limited. Confining the therapeutic approach to relief of symptoms is reasonable.

Given the paucity of effective standard treatment options, encourage patients to enroll in clinical trials. Radiotherapy, chemotherapy, and chemoradiotherapy have been tried, but response rates probably are low, and an effect on survival is questionable.

Long-Term Monitoring

Follow-up guidelines are not well established for ampullary carcinoma. Reasonable practice includes blood studies, chest radiograph/computed tomography (CT) scan, and CT scan of the abdomen and pelvis every 6 months.

If treatment ultimately fails, it often does so within 5 years. Unfortunately, good salvage therapies do not yet exist. Palliative chemotherapeutic agents and effective medications for pain relief exist.