Periampullary Tumors

Etiology

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.[1]

Epidemiology

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.[2]

Histopathology

The histology of ampullary cancers commonly resembles that of adenocarcinomas of intestinal origin rather than pancreaticobiliary origin.[3] 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.[4] The later is associated with a worse prognosis.[1] These cancers are thought to arise from premalignant precursor lesions-ampullary adenomas. These tumors commonly associated with K-ras mutations.[5]

History and Physical

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.[6]

Evaluation

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.

Treatment / Management

Surgery offers the chance of curing this disease at an early stage. However, approximately 45 percent of the treated population develops recurrence over time.[7] 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.

Differential Diagnosis

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.

Surgical Oncology

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.[8] 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.[9]

Radiation Oncology

 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.[10] 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.[11]

Pertinent Studies and Ongoing Trials

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.

Medical Oncology

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.

Staging

Martin proposed a 4-stage system.

• 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 the 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

Prognosis

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.[12] Recently the role of histology phenotype has emerged with some data indicating poor prognosis associated with pancreaticobiliary histopathology compared to intestinal type.

Complications

Ampullary cancer often causes biliary obstruction. Other complications include that of the surgery, chemotherapy and radiation treatment.