Ampullary cancer arises from ampulla of Vater terminal to the confluence of the distal common bile duct (CBD) and the pancreatic duct. It is important to distinguish ampullary carcinoma from periampullary tumors such as extra-biliary or pancreatic tumors due to wide variation in clinical outcomes and therapeutic management. For instance, pancreatic cancers and biliary tract tumors such as cholangiocarcinoma are associated with significantly worse prognosis with limited treatment options compared to ampullary cancers, even in early disease presentations. Recent studies further evaluated histological variation depending on the epithelium of origin. Ampullary carcinoma is commonly intestinal epithelial at about 47 percent or pancreato-biliary epithelial subtypes at about 24 percent.
The incidence is rare and accounts for 6 percent that arises in the periampullary area. These tumors commonly occur sporadically, however, a genetic predisposition such as hereditary polyposis syndrome or hereditary nonpolyposis colorectal cancer can raise the incidence risk to 200 fold.
This disease occurs commonly in 7th decade of life unless in the setting of any predisposing syndrome where it presents earlier age. This is likely due to screening programs for this particular subset of the population.
The histology of ampullary cancers commonly resembles that of adenocarcinomas of intestinal origin rather than pancreaticobiliary origin. Likewise, the biologic behavior of these tumors often resembles intestinal than the pancreaticobiliary phenotype. The histology is differentiated by the expression of cyclooxygenase-2 (COX-2) by ampullary cancers that points towards intestinal origin than pancreato-biliary origin. The later is associated with a worse prognosis. These cancers are thought to arise from premalignant precursor lesions-ampullary adenomas. These tumors commonly associated with K-ras mutations.
The common presenting symptom at the time of diagnosis is obstructive jaundice due to distal biliary ductal blockage, which prompts further evaluation for diagnosis. These tumors can be associated with diarrhea, weight loss, pain radiating to back, occult gastrointestinal bleeding, and fatigue.
The TNM system of the American Joint Committee on Cancer (AJCC) is used to stage these cancers. The diagnosis is established with endoscopic ultrasound / Endoscopic retrograde cholangiopancreatography (ERCP) and fine-needle aspiration cytology (FNAC). If a patient presents with obstructive jaundice, these modalities could allow therapeutic intervention will be done at the time of diagnostic evaluation with biliary stent placement. As most of the patients undergo surgery, temporary plastic stents are preferred to metallic stents. All patients diagnosed with ampullary cancers need staging evaluation with computerized tomography (CT) of chest, abdomen, and pelvis. Often clear differentiation of primary ampullary cancers from other periampullary malignancies such as those arising in the pancreas, biliary duct, or intestine is challenging at the time of diagnostic evaluation.
Surgery offers the chance of curing this disease at an early stage. However, approximately 45 percent of the treated population develops recurrence over time. Therefore, a subset of patients could potentially get benefited from adjuvant treatment modalities such as chemoradiation or chemotherapy. It is difficult to evaluate for single best treatment modality in adjuvant setting as exclusive randomized controlled trials were not available due to the rarity of this disease. The evidence of benefit is derived from retrospective data or combined series of randomized data when these tumors were treated along with other periampullary cancers. Surgical resection is not feasible for advanced disease with distant metastasis, and these tumors are treated with systemic chemotherapy regimens that are used to treat pancreatic cancer or colorectal cancers.
The clinical presentation of ampullary cancers often resembles the presentation of distal biliary ductal cancers (cholangiocarcinomas), pancreatic cancers, or colon cancers. Often the FNAC is difficult to differentiate ampullary from other periampullary cancers. Definitive surgery allows prospectively identifying histology accurately. From the biologic behavior standpoint, ampullary cancers are associated with a better prognosis compared to other periampullary malignancies.
The only curative potential treatment modality for ampullary cancer is surgical resection with pancreaticoduodenectomy/Whipple with or without preserving the pylorus. Surgical outcomes are better in high volume centers. The perioperative mortality is less than 5%; however, the perioperative morbidity is 20 to 40 percent with anastomotic leak and delayed gastric emptying as a common source. As this cancer commonly occurs in the 7th decade, elderly patients with medical comorbidities, limited data are available to treat with less aggressive approaches such as ampullectomies. There is little evidence about neoadjuvant therapy in a small subset of patients; however, at this time, there are no guidelines in consensus. an interprofessional evaluation is recommended to identify the patients who may be benefited from this modality.
Radiation is an option for the selected subset of patients who are at high risk for recurrences such as positive or close surgical margin or positive nodal disease. However, the definitive evidence on the overall clinical benefit lacks due to the relative rarity of this disease and the lack of large randomized studies. The commonly used dose is 50.4 grays given in 4 to 6 weeks concurrently with fluoropyrimidine or gemcitabine-based treatment in adjuvant setting either sandwiched between chemotherapy or after 4 to 5 months of chemotherapy.
Exclusive randomized controlled trials for ampullary cancer are lacking. It could be challenging as this tumor is rare in incidence. Clinical studies are mostly single-institution retrospective studies or combined randomized studies for advanced cancers with other periampullary tumors.
Ampullary cancer patients with T2 or above stage or lymph node-positive tumors are associated with increased recurrence risk and therefore, could be benefitted from adjuvant treatment. A common strategy in the United States is adjuvant chemotherapy with gemcitabine or fluoropyrimidine for 6 months if systemic therapy alone is chosen. Patients presented with large tumors, positive margins, and node positivity are currently being treated with adding 6 weeks of concurrent chemoradiation eight upfront or the end of systemic chemotherapy.
The American Joint Committee on Cancer staging system uses the TNM system.
Martin proposed a 4-stage system.
The prognostic outcome is dependent upon the extent of local invitation, the status of surgical margins after the definitive surgery, and the presence of nodal metastasis. Node positivity is a key factor in determining the overall prognosis. The five-year survival rate range from 70% to 80% for node-negative disease compared to 20% to 50% for node-positive disease. Recently the role of histology phenotype has emerged with some data indicating poor prognosis associated with pancreaticobiliary histopathology compared to intestinal type.
Ampullary cancer often causes biliary obstruction. Other complications include that of the surgery, chemotherapy and radiation treatment.
There are no specific guidelines existing for post-treatment surveillance. Many oncologists follow patients every 3 to 6 months for patient’s high risk for recurrence for about 5 years. Surveillance endoscopy is recommended after local resection every six months for two years and then annually for an additional 3 to 5 years. The utility of frequent CT scans for surveillance is less clear.
Ampullary cancers commonly present in the elderly age group. Any change in color of urine or yellowish discoloration of skin should prompt further medical evaluation as jaundice could be presenting symptoms. This cancer could be cured if presented at an early stage, therefore mandates prompt diagnostic and surgical evaluations.
The management of ampullary cancer requires interprofessional attention involving interventional gastrointestinal medicine at the diagnostic level and medical oncology, surgical oncology, and radiation oncology at the management level. This needs thorough care coordination among all the disciplines for outlining and conducting a patient-centered personalized treatment strategy. Adjuvant chemotherapy with or without radiation plays a crucial role in resected ampullary carcinoma that improves overall clinical outcomes. For advanced tumors, due to the rarity of these tumors, currently, the data is limited to the treatment regimens used for pancreatic cancer. At this time, there is no consensus regarding optimal management and therefore mandates an interprofessional evaluation.
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