Periampullary cancers encompass a mixture of cancers but in general are separated into four subtypes: cancer in the head of the pancreas, distal bile duct cancer, true ampullary cancer, and duodenal cancer. These cancers arise in the vicinity of the ampulla of Vater and are differentiated by their histologic origins (pancreatic, distal bile duct, ampulla of Vater, or duodenum). While pancreatic adenocarcinoma makes up the majority of resected periampullary cancers at 62%, ampullary cancer accounts for 19%, distal bile duct cancer 12%, and duodenal cancer 7% of resected periampullary cancers.¹ Although preoperative assessment with imaging and biopsy can distinguish one subtype from the other, often times the tumor origin may be undetermined preoperatively. Moreover, duodenal cancer in the periampullary region as well as intestinal-type ampullary cancer behave in a similar fashion, whereas distal bile duct cancer and pancreaticobiliary-type ampullary cancer behave similar to one another. While 56% of small bowel adenocarcinomas arise in the duodenum, small bowel adenocarcinoma only comprises 2% of all gastrointestinal cancers in the United States.² This chapter focuses on duodenal adenocarcinoma as well as intestinal-type ampullary cancer, as all other duodenal cancers and periampullary cancers are beyond the scope of this chapter.

Small bowel cancer accounts for 3.1% of all intestinal cancers. Of the malignant small intestinal neoplasms, neuroendocrine tumor accounts for 36.5%, adenocarcinoma 30.9%, lymphoma 18.7%, sarcoma and gastrointestinal stromal tumor 10.0%, and miscellaneous and nonspecified 1.1%.³ Although neuroendocrine tumor surpasses adenocarcinoma as the most common cancer of the small intestine, adenocarcinoma is the most common cancer of the duodenum.⁴

Small bowel adenocarcinoma is rare. However, based on the Surveillance, Epidemiology, and End Results (SEER) registry, the incidence increased from 0.49 to 0.66 per 100,000 people from 1973 to 2004.³ Duodenal adenocarcinoma accounts for the majority of the small bowel adenocarcinomas (~50%), which is followed by jejunal (~20%) and ileal (~15%) adenocarcinoma. Duodenal adenocarcinoma is more common in men (60%) with a median patient age of 67 years at presentation. The majority of duodenal adenocarcinoma arises in Caucasians.^3,4

Ampullary cancer is quite rare as well, comprising only 0.5% of all gastrointestinal malignancies. From 1973 to 2005, 5,625 cases of ampullary cancer were reported to the SEER registry. During this period of time, the incidence increased from roughly 0.4 to 0.55 per 100,000 persons. Ampullary cancer is more common in men and increases in incidence after the age of 35. A slight predominance for Caucasians is present as well.⁵

Several factors have been implicated in increasing an individual’s risk of developing duodenal and ampullary cancer during a lifetime. Although the duodenum accounts for only 8% of the intestinal length, the majority of small bowel adenocarcinomas occur within the duodenum. More specifically, 57% of duodenal adenocarcinomas occur within the second portion of the duodenum in the periampullary location, followed by the third and fourth portions of the duodenum, with cancers of the first portion of the duodenum being rare. Most duodenal adenocarcinomas are sporadic, arising from the accumulation of multiple somatic mutations as a result of intestinal luminal exposure to carcinogens. The duodenum is presumably at the greatest risk of developing adenocarcinoma within the small intestinal tract because it is exposed to potentially caustic agents first, such as ingested carcinogens, biliary and pancreatic secretions, and gastric acids. Similar to colorectal adenocarcinoma, most small bowel adenocarcinomas and intestinal-type ampullary cancers arise in the setting of an adenoma and undergo molecular and genetic transformation from an adenoma to invasive adenocarcinoma. The risk of an adenoma undergoing malignant transformation increases with larger size and the presence of villous features, similar to colorectal adenocarcinoma.

In other instances, adenocarcinoma of the duodenum may arise as a component of polypoid conditions such as familial adenomatous polyposis. Familial adenomatous polyposis is an inherited condition in which patients have a 24% to 100% risk of developing duodenal adenomas with a predilection for the ampullary region. This increases the risk of developing duodenal adenocarcinoma by 331-fold. Peutz–Jeghers syndrome, celiac sprue, and hereditary nonpolyposis colorectal cancer can also increase the lifetime risk of developing duodenal adenocarcinoma.⁶

An important risk factor contributing to the development of small bowel adenocarcinoma is Crohn’s disease, increasing the risk up to 100-fold. Adenocarcinoma in the setting of Crohn’s disease generally develops in the diseased segments of bowel harboring dysplastic changes. Although Crohn’s disease generally affects the ileum, one quarter of Crohn’s-associated adenocarcinomas arises in the duodenum and jejunum. Unfortunately, Crohn’s-associated adenocarcinoma portends a worse prognosis due to delay in diagnosis. Often times, symptoms related to the cancer are mistaken for common Crohn’s-related symptoms.⁶

While sporadic tumors account for the majority of duodenal adenocarcinomas and ampullary cancers, certain inherited syndromes increase a person’s risk for developing these malignancies. These inherited syndromes develop as a result of single, specific germline mutations. In the setting of familial adenomatous polyposis, a germline mutation in the adenomatous polyposis coli (APC) gene promotes tumor formation in the large intestine as well as the duodenum. However, only 2.5% to 4.0% of duodenal adenocarcinomas are believed to arise in the setting of familial adenomatous polyposis.⁶ Peutz–Jeghers syndrome is an autosomal dominant polyposis syndrome leading to multiple hamartomatous polyps throughout the small and large intestine, markedly increasing the risk of developing adenocarcinoma. Hereditary nonpolyposis colorectal cancer results from the loss of DNA mismatch repair, increasing the risk of small bowel adenocarcinoma, colorectal cancer, and endometrial cancer. Of note, the expression of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are elevated in only about one-third of patients with duodenal adenocarcinoma.²

Ampullary cancers can be further classified as pancreaticobiliary or intestinal-type. The clinical behavior of the tumor reflects this classification with intestinal-type having a much better prognosis, mimicking that of duodenal adenocarcinoma, and pancreaticobiliary-type having a more aggressive course, mimicking that of pancreatic adenocarcinoma.⁷ The expression of CEA, CA 19-9, Ki-67, and p53 was studied in 45 patients with ampullary cancer. Tumors expressing CA 19-9 correlated with a significantly worse 5-year overall survival compared to those that did not (36% vs. 100%) due to pancreatic involvement or likely pancreaticobiliary differentiation. Patients with a noninvasive adenomatous component to their tumors had a significantly better prognosis than those who did not (68% vs. 27%). The tumors without an adenomatous component presumably represented aggressive tumors rapidly progressing to destroy the underlying adenomatous tissue from which it arose, or they could represent tumors which did not arise from an adenoma. Either situation indicates a more aggressive tumor and dismal prognosis.⁸

Diagnosing duodenal adenocarcinoma and ampullary cancer, intestinal-type versus pancreaticobiliary-type, requires thorough histopathologic evaluation and immunohistochemical staining of tissue specimens. The two studies below report typical pathologic findings for duodenal adenocarcinoma and ampullary cancer.

On pathologic evaluation of 122 patients undergoing pancreaticoduodenectomy for duodenal adenocarcinoma at a single-institution, four patients (3%) had T1, 17 (16%) T2, 55 (51%) T3, and 32 (30%) T4 tumors. Median tumor size was 4 cm. Nodal metastases were noted in 79 patients (65%) with 24 patients (22%) having four or more positive nodes. Thirty-seven percent of patients had perineural invasion, while 39% had microvascular invasion. Tumors were well-differentiated in four patients (4%), moderately differentiated in 68 patients (60%), and poorly differentiated in 41 patients (36%). Ten patients (8%) had positive margins, five with microscopically positive margins and five with macroscopically positive margins.²

On pathologic evaluation of 450 patients undergoing surgical resection of ampullary adenoma or adenocarcinoma in a single-institution, 347 patients (77.1%) had ampullary adenocarcinoma. Median tumor size was smaller for invasive adenocarcinoma (2.0 cm) versus adenoma (2.9 cm). Sixty-one of the 347 patients with invasive adenocarcinoma (17.6%) had an associated adenoma present. Among those diagnosed with invasive ampullary adenocarcinoma, half of the patients had either T1 (9.2%) or T2 (41.1%) disease. Regional lymph node metastases (N1) were present in 189 of the 347 patients (54.4%). Perineural invasion was noted in 99 patients (41.4%) of the 347 patients with invasive ampullary cancer, and microvascular invasion was noted in 104 patients (43.6%). The majority had either well-differentiated (5.1%) or moderately differentiated (56.8%) tumors. 96.1% of patients undergoing pancreaticoduodenectomy had an R0 resection.⁹

Although commonly occurring in the second portion of the duodenum, patients with duodenal adenocarcinoma present with clinical manifestations which slightly vary from those with ampullary cancer. The most common presenting symptoms of duodenal adenocarcinoma are abdominal pain (39%), weight loss (35%), jaundice (25%), duodenal obstruction (25%), and upper gastrointestinal bleeding (24%). In the setting of preoperative upper gastrointestinal bleeding, the intraoperative blood transfusion rate is higher at 48%.²

Patients with ampullary cancer are more likely to present with jaundice (72.3%), weight loss (42.3%), pruritus (15.4%), and nausea or vomiting (14.2%). They were much less likely to present with gastrointestinal bleeding (3.4%) compared to patients with duodenal adenocarcinoma. Rarely, patients with ampullary cancer present as an incidentaloma (3.1%). In addition, patients with invasive ampullary adenocarcinoma are more likely to require biliary drainage for obstructive jaundice compared to those with an adenoma (78.1% vs. 43.2%).⁹

Staging for both duodenal adenocarcinoma and ampullary cancer is based on the American Joint Committee on Cancer (AJCC) TNM staging classifications. Duodenal adenocarcinoma staging is based on the staging for small bowel adenocarcinoma (Table 103-1). Ampullary cancer has its own staging system, which emphasizes the importance of pancreatic invasion in prognosis (Table 103-2).¹⁰