Ampullary Carcinoma

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