Ampullary Carcinoma Treatment & Management

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