Periampullary adenocarcinomas are a set of neoplasms that arise near the ampulla of Vater. Although they are all adenocarcinomas, they arise from the different mucosal tissues of the pancreatic duct, bile duct, ampulla, and duodenum. They are often discussed together because they often share a common clinical presentation, they can be hard to distinguish on cross-sectional imaging, and when respectable, they are treated with pancreaticoduodenectomy.

Pancreatic adenocarcinoma is by far the most common of the 4 periampullary tumors. In fact, in 2016, it became the third most common cause of cancer death in the United States, and it is predicted that in the near future, it will become the second most common cause of cancer death.¹ Pancreatic adenocarcinoma accounts for a vast majority of the periampullary cancers, with the other 3 types being much less frequent. The 4 cancers have different resectability rates and long-term survival rates. Long-term survival is dependent on where cancer arose from, stage at diagnosis, degree of differentiation, and ability to completely resect cancer with negative margins.

In addition to these 4 types of adenocarcinomas, other less common tumors arise in the periampullary region including neuroendocrine tumors, acinar cell cancers, squamous cell carcinomas, gastrointestinal tumors, lymphoma, and metastases from other sites.

Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma is the third leading cause of cancer death in the United States. In 2016, there will be an estimated 53,000 new cases diagnosed with 42,000 deaths from this disease.^1,2 The peak incidence of pancreatic cancer occurs in the seventh decade of life. African Americans have a higher risk of developing pancreatic ductal adenocarcinoma than do whites. There is a slightly higher incidence in men compared to women. The lifetime risk of developing pancreatic cancer is 1 in 65 and 1 in 67 in men and women, respectively, in the United States. Smoking is one of the strongest risk factors for the development of pancreatic cancer. Obesity has also been implicated, and other factors, such as diabetes and alcohol use, have also been implicated.

It is estimated that up to 10% of patients who develop pancreatic ductal adenocarcinoma have a familial predisposition. In the majority of these families, the genetic predisposition has not been identified. We do know, however, that mutations in the following genes can increase the risk of pancreatic cancer: BRCA2 (familial breast and ovarian cancer), PRSS1 (hereditary pancreatitis), p16 (familial atypical multiple mole and melanoma), and HNPCC (hereditary nonpolyposis colorectal cancer).³

Distal Bile Duct Cancer (Cholangiocarcinoma)

Distal cholangiocarcinoma is the second most common of the periampullary adenocarcinomas. Bile duct cancers or ­distal cholangiocarcinomas are typically grouped into 3 forms based on anatomic origin. Peripheral or proximal bile duct adenocarcinomas arise in the intrahepatic biliary tree. ­Perihilar cholangiocarcinomas arise near the bifurcation of the right and left bile ducts. Distal cholangiocarcinomas arise in the most distal part of the bile duct from the junction of the cystic duct to the ampulla of Vater. The incidence of cholangiocarcinoma is much less than that of pancreatic adenocarcinoma.⁴ Approximately 30% of bile duct adenocarcinomas are diagnosed as arising in the distal bile duct. It is a disease of the elderly, with a peak incidence in the seventh decade of life. Risk factors for the development of cholangiocarcinoma include sclerosing cholangitis, choledochal cysts, hepatolithiasis, and infestation with liver flukes.⁵ The common etiologic factor with these conditions is continued long-term chronic inflammation.

Adenocarcinoma of the Ampulla of Vater

Ampullary adenocarcinoma is the third most common of the periampullary malignancies.⁶ These cancers are slightly more common in males and have a peak incidence in the seventh decade of life. These cancers tend to cause symptoms of obstructive jaundice relatively early in their course, so they tend to be discovered at a smaller size and earlier stage. Additionally, they tend to have less biologic aggressiveness than pancreatic and distal bile duct adenocarcinomas. Several groups have further subdivided adenocarcinomas into various histologic subtypes including pancreatic, biliary, intestinal, and gastric. Patients with the intestinal subtype have much better prognosis than patients with the other subtypes.

Duodenal Adenocarcinoma

Duodenal adenocarcinomas are the least common of the 4 periampullary malignancies discussed in this chapter. They are equally prevalent in men and women and have a peak incidence in the seventh decade. These cancers can arise from benign polyps, as in the colon. Patient with duodenal adenocarcinoma, especially if they have multiple polyps, should be ruled out for familial adenomatous polyposis syndromes.

Patients with duodenal adenocarcinoma can present with gastric outlet obstruction and/or with jaundice if it arises right next to the ampulla. Duodenal adenocarcinomas tend to be larger at diagnosis than pancreatic, biliary, and ampullary adenocarcinomas because of the lack of symptoms until significant intraluminal growth. Patients with duodenal adenocarcinoma have much better prognosis, stage for stage, than patients with pancreatic and biliary adenocarcinomas.

Clinical Presentation

The signs and symptoms associated with periampullary and pancreatic tumors tend to be nonspecific, which often contributes to a delay in diagnosis. Presenting symptoms are commonly jaundice and vague mid-epigastric abdominal pain. Unfortunately, by the time such symptoms are manifest, the tumor is often in its late stages, with an estimated 80% of patients presenting with metastatic or unresectable disease.⁷ The combination of jaundice (painless or painful) with pruritus, acholic stools, and tea-colored urine in the absence of acute biliary disease is a constellation of symptoms that should prompt the suspicion of a periampullary tumor. Upon further questioning, a history of vague pain and unintended weight loss is often present. Often, a more severe and persistent mid-epigastric pain that radiates to the back indicates a more advanced tumor. Other relatively nonspecific symptoms such as malaise, fatigue, anorexia, indigestion, or early satiety are often noted upon evaluation. Signs of pancreatic insufficiency (malabsorption, frequent fatty or floating stool) would suggest obstruction of the main pancreatic duct, whereas nausea and vomiting would suggest gastric outlet or duodenal obstruction. A quite subtle sign, but one that is now known to be associated with the ultimate diagnosis of pancreatic malignancies, is the rather sudden development of adult-onset diabetes in previously healthy patients in their sixth decade of life.⁸

The location of the tumor will often influence the signs and symptoms of presentation. For example, tumors in the body and tail of the pancreas are more likely to present at a later stage, with larger tumors contributing to more abdominal pain and weight loss. However, tumors that occur within or adjacent to the distal bile duct tend to present at an earlier stage and manifest as painless jaundice.

Physical exam findings include scleral icterus, jaundice, and skin excoriation from pruritus and scratching. The Courvoisier sign, noted by palpation of an enlarged gallbladder, may be present without peritoneal signs. More advanced disease may include the findings of cachexia, palpable left supraclavicular lymph nodes (Virchow node), palpable periumbilical nodes (Sister Mary Joseph node), and palpable pelvic metastatic disease on a rectal exam (Blumer shelf).

Laboratory Evaluation

Patients who present with signs of biliary obstruction are initially evaluated with basic laboratory testing including a complete blood count, electrolytes, liver function tests, albumin, and prothrombin time. If separate testing suggests a periampullary or pancreatic mass, then additional laboratory values that may be useful include tumor markers such as carbohydrate antigen CA 19-9, carcinoembryonic antigen (CEA), or chromogranin A (if a neuroendocrine tumor is suspected).

Extrahepatic biliary obstruction generally results in hyperbilirubinemia with the direct (or conjugated) bilirubin being more elevated than the indirect (or unconjugated) bilirubin. In addition, the alkaline phosphatase is generally more significantly elevated with extrahepatic biliary obstruction than the transaminases (alanine aminotransferase or aspartate aminotransferase). The prothrombin time or international normalized ratio (INR) may be abnormal due to malabsorption of fat-soluble vitamins such a vitamin K. Hypoalbuminemia from malabsorption and weight loss may be present. While the tumor marker CA 19-9 may be helpful, its sensitivity and specificity can be limited by certain conditions. First, the blood test for CA 19-9 is dependent on the Lewis blood group antigen phenotype and is not detectable in patients with Lewis AB– phenotype (approximately 5%-10% of the population). Second, biliary obstruction artificially elevates CA 19-9 levels, and therefore, it is not a reliable tumor marker in the presence of an ongoing obstruction. After relief of the biliary obstruction and subsequent normalization of the bilirubin, CA 19-9 may then become a more reliable tumor marker. Other conditions such as inflammation, cholangitis, and nonpancreatic tumors (gastrointestinal, ovarian) are also associated with increased CA 19-9 levels. Therefore, CA19-9 can support a diagnosis of periampullary or pancreatic adenocarcinoma but it should not be used to infer the actual diagnosis. An elevated CA 19-9 may be useful for monitoring response to therapy or for monitoring disease progression.

Imaging Evaluation

Accurate imaging of periampullary and pancreatic tumors is essential for optimal treatment planning. Well-done imaging provides information about the extent of disease and staging estimation and assists the surgeon in determining the potential for a complete resection. A dedicated, fine-cut, 3-phase pancreas protocol computed tomography (CT) scan provides valuable information regarding local (primarily vascular) and regional (primarily the liver as the most common site of metastasis) spread of disease (Fig. 73-1).⁹ Alternatively, for patients with CT contrast allergy or renal insufficiency, a magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP) study can provide similar information (Fig. 73-2). In the absence of metastatic disease, attention is paid to the local vasculature that will affect operative planning. Namely, the relationship of the tumor to the inferior vena cava (IVC), portal vein (PV), superior mesenteric vein (SMV), superior mesenteric artery (SMA), celiac trunk, and hepatic artery is assessed. Signs of abutment or invasion of these vessels is not a direct contraindication for resection, but these tumors are considered borderline resectable and the neoadjuvant treatment planning and the operative technique will likely be altered (Fig. 73-3).¹⁰ For locally advanced adenocarcinoma of the pancreas, we favor a neoadjuvant approach to test the biology of the tumor and attempt to downstage the tumor before considering a resection.¹¹

Additional imaging with endoscopic ultrasound (EUS) and concomitant fine-needle aspiration (FNA) biopsy can both add valuable information regarding the relationship of the tumor to the mesenteric vessels and simultaneously confirm a tissue diagnosis. Biopsy confirmation is not always necessary for resectable lesions; however, the treatment approaches to neuroendocrine tumors, lymphomas, and other tumors that occur in the periampullary and pancreatic region vary significantly such that biopsy is often warranted.

The routine use of positron emission tomography (PET) combined with CT for periampullary and pancreatic tumors is common, but its ultimate utility is still being debated.¹² The lack of resolution and fine detail around the vasculature is such that the need for a pancreas protocol contrasted CT scan is not obviated. However, PET-CT may be useful in resolving suspicious potentially metastatic lesions noted on other imaging modalities (Fig. 73-4). Despite the use of improved imaging techniques (including PET-CT), small subcapsular liver nodules or occult peritoneal implants are still discovered in approximately 10% to 20% of patients who meet operative criteria.¹³

Biliary Decompression and Tissue Diagnosis

Jaundice is often the first presenting sign for periampullary tumors prompting further diagnostic and therapeutic interventions. The advantage of endoscopic retrograde cholangiography (ERC) is that it directly evaluates the periampullary region. Periampullary adenomas, adenocarcinomas, or other lesions may be visualized for direct biopsy. ERC may also be useful for diagnosing and treating benign causes of jaundice such as choledocholithiasis or inflammatory conditions such as primary sclerosing cholangitis. At ERC, tumors involving the distal bile duct region often demonstrate an abrupt (as opposed to smoothly tapered) cutoff suggestive of malignancy (Fig. 73-5). The double duct sign (dilation of the extrahepatic common bile duct and the pancreas duct) is most often a sign of malignancy (Fig. 73-6).¹⁴ ERC also provides the opportunity for biopsy or brushing of the bile duct to obtain a tissue diagnosis. If a definitive diagnosis is not obtained at ERC and is desired for treatment ­planning, then other approaches such as EUS with FNA or direct ­cholangioscopic-guided biopsy may be necessary.

The need for biliary stenting depends on staging, the patient’s condition, and the timing of potential surgical resection. Patients with metastatic or locally advanced tumors will benefit from stenting, and the immediate relief from the obstruction allows for the patient’s symptoms to improve while the remainder of the evaluation is conducted. Most patients are grateful for the symptom relief from pruritus, malabsorption, scleral icterus, and changes in stool color, although this can take several days to weeks depending on the degree of acquired liver dysfunction. For patients presenting with resectable disease, the value of routine preoperative stenting is an area of controversy. A recent prospective randomized trial in pancreatic cancer patients presenting with a total bilirubin level of 2.3 to 14.6 mg/dL found that routine preoperative stenting was associated with an increase in serious complications with no change in mortality or length of stay compared to patients who went straight to surgery within 7 days of diagnosis.¹⁵ Select patients with resectable tumors may still benefit from biliary stenting if they have evidence of cholangitis, intractable pruritus, or significant nutritional deficiencies or if surgery cannot be arranged in a timely (<7 days) fashion.

Laparoscopy

The use of staging or diagnostic laparoscopy varies significantly from provider to provider and institution to institution. Proponents of the technique argue that it can potentially save some patients from the morbidity of a nontherapeutic exploratory laparotomy. Opponents of routine staging laparoscopy argue that improvements in cross-sectional imaging have significantly reduced the number of patients discovered to have occult metastasis and that the extra cost and inefficient use of operative room time do not justify the added expense. Most high-volume pancreatic and hepatobiliary centers employ a selective approach to staging laparoscopy.¹⁶ The likelihood of finding metastatic disease is relatively greater in patients with larger tumors of the body and tail of the pancreas or patients with markedly elevated CA 19-9 (>200 U/mL).

Whipple Procedure

A potentially curative pancreaticoduodenectomy is the preferred approach to resectable periampullary carcinomas. An upper midline or bilateral subcostal incision is used to gain access to the abdomen. The primary survey for an occult metastatic disease is conducted by exploring the entire abdomen with particular attention to the liver, omentum, peritoneal surfaces, and base of the transverse mesocolon. The secondary survey assesses the involvement of the tumor with the adjacent mesenteric vessels. The exact sequence of secondary assessment may vary depending on preoperative imaging and suspicion of potential vascular involvement; however, a consistent and systematic approach is favored to reduce variability and enhance reliability.^17,18

The duodenum is mobilized and a Kocher maneuver is performed to assess the relationship of the tumor to the SMA and retroperitoneal structures such as the IVC, right renal vein, and aorta. Following this, the SMV is located as it courses posterior to the neck of the pancreas. It may be helpful to lift up the transverse mesocolon and follow the middle colic vein until it enters the SMV. The tunnel under the neck of the pancreas is cleared by gentle blunt dissection of the SMV away for the posterior neck of the pancreas. The PV assessment on the superior aspect of the pancreas is generally accessed after first ensuring that the common hepatic artery is clear of tumor involvement. The common hepatic artery is identified coursing parallel and close to the superior border of the pancreatic head. Tracing the hepatic artery leads to the gastroduodenal artery tracking in a caudal direction. The gastroduodenal artery is dissected near its origin from the proper hepatic artery and test clamped to ensure adequate flow through the hepatic artery prior to dividing the gastroduodenal artery. Division of the gastroduodenal artery allows for better visualization of the PV and subsequent creation of a tunnel on the cephalad side of the pancreas neck to connect with the prior SMV dissection from below. At this point, the major vascular structures have been evaluated, and an assessment is made regarding the chances of achieving a margin-negative resection with or without the need for vascular reconstruction. If necessary, the procedure can be abandoned at this juncture since no enteric structures have been divided.

Once the decision has been made to proceed with pancreaticoduodenectomy, a cholecystectomy is performed and the common bile duct is encircled, dissected free, and divided around the level of the cystic duct insertion. The decision to perform a pylorus-preserving versus classic Whipple procedure is contingent on local tumor extent and surgeon preference. Each approach has its relative proponents and opponents.¹⁹ If the tumor is well away from the pylorus, a pyloric-preserving approach may be taken by dividing the duodenum 1 to 2 cm beyond the pylorus with a stapling device. If tumor encroaches upon the pylorus, then a wider margin (classic Whipple) with the division of the stomach to include the antrum with the specimen is undertaken. The right gastroepiploic vessels are divided to allow retraction of the stomach out of the field. The previously dissected tunnel posterior to the neck of the pancreas is reaffirmed, and hemostatic stay sutures are placed along the superior and inferior edges of the pancreatic neck to control bleeding, provide retraction, and facilitate exposure of the SMV. While protecting the SMV, the pancreatic neck is divided sharply so that the main pancreatic duct can be easily identified. A frozen section of the pancreatic duct margin is sent early such that additional pancreatic margins may be obtained before reconstruction. Cautery is applied to control the small vessels bleeding from the cut edge of the pancreas.

Moving approximately 15 to 20 cm distal to the ligament of Treitz, the jejunum is divided with a stapling device. The proximal jejunum and fourth portion of the duodenum are separated from the root of the mesentery using clips or a cautery device to control the many small vessels going to the jejunum. The intestine to be removed with the specimen is passed posterior to the root of the mesentery and into the right upper quadrant. The attachments from the head and uncinate process of the pancreas are carefully dissected away from the SMV and PV, clipping or ligating small venous branches. The duodenum and uncinate process are rotated out of the retroperitoneum to allow dissection along the lateral border of the SMA. Working in a combination of both anterior and posterior approaches, the final attachments of the pancreas to the SMA and SMV/PV are separated. A search for any additional regional lymph nodes is made to ensure an adequate lymph node dissection. Extensive periaortic and vena cava lymph node dissections are not necessary as they have not been shown to improve survival.²⁰ The specimen is oriented and marked to facilitate pathologic analysis. Careful examination of the retroperitoneal margin is of crucial importance.

Reconstruction is commenced by passing the divided jejunum either through the transverse mesocolon to the right of the middle colic vessels or posterior to the mesenteric vessels to lay in the right upper quadrant as an upside down “J.” The body of the pancreas is freed from the splenic vein for approximately 2 cm to provide length for the jejunal anastomosis. An end pancreas to side of jejunum anastomosis is prepared for a mucosa-to-mucosa connection. Fine-caliber absorbable suture is used on the mucosa in an interrupted fashion. Although routine pancreatic duct stenting has not been shown to reduce pancreatic fistula rates,²¹ in some patients with a soft pancreatic gland or a small pancreatic duct, a pediatric feeding tube may be sized to the pancreatic duct, trimmed to about 6 cm, and fixed in place across the anastomosis. An outer layer of a permanent suture is used on the serosa and pancreatic capsule to buttress the pancreas against the jejunum. The internal pancreatic stent will generally pass unnoticed in the stool several weeks later.

The hepaticojejunostomy is created about 5 to 10 cm away from the pancreaticojejunostomy. Because the common bile duct has often been obstructed, the bile duct is often dilated and fibrotic, thus facilitating the anastomosis. This is generally performed in a side jejunum to end common bile duct manner, with a duct-to-mucosal anastomosis using a fine absorbable monofilament in either a running or interrupted fashion. If the bile duct was not obstructed, a small internal stent similar to that used for the pancreatic duct anastomosis may also be used. A few buttressing absorbable outer sutures are placed to hold the jejunum in place against the hilum of the liver.

Reconstruction of the stomach or duodenum to the jejunum is accomplished in an antecolic manner about 20 to 25 cm downstream to the biliary anastomosis. This may be done using stapling devices or with a 2-layer hand-sewn technique according to surgeon preference. Closed suction drains are placed around the pancreatic and biliary anastomoses in an effort to control potential biliary or pancreatic fistulae, which are responsible for much of the morbidity and mortality associated with this operation.²² Figure 73-7 shows the steps of the Whipple operation with reconstruction.

Distal Pancreatectomy

For cancers of the pancreatic body and tail, a distal pancreatectomy and splenectomy compose the preferred operative approach. For benign conditions of the pancreas or very small neuroendocrine tumors, a spleen-preserving distal pancreatectomy may be considered. The reported advantage of preserving the spleen is due to the potential risk of postsplenectomy sepsis. However, removing the spleen with the tail of the pancreas simplifies the procedure and reduces the risk of significant bleeding associated with the tedious dissection of the splenic artery and vein along the pancreas. ­Furthermore, the potential for postsplenectomy sepsis in adults is quite low, and this risk can be further mitigated through the administration of vaccination for pneumococcus, Haemophilus meningitides, and Haemophilus influenzae. For adenocarcinomas and larger neuroendocrine tumors in the pancreas, including the splenectomy enhances the removal of prognostically relevant regional peripancreatic lymph nodes.

Diagnostic and therapeutic laparoscopy can be very useful for tumors in the body and tail of the pancreas. Access to the abdomen can be made by inserting the laparoscope near the umbilicus for the initial exploration to rule out occult metastatic disease. A decision can then be made to proceed with a resection using laparoscopic techniques or converting to an open approach. Similar operative principles apply to either technique. Depending on the size and location of the tumor, either a midline incision or a left subcostal incision may be selected. The lesser sac is entered and the colon is dissected free from the attachments to the stomach and spleen. The short gastric vessels are divided, and the peritoneal attachments between the posterior stomach and anterior pancreas are opened to allow retraction of the stomach cephalad. The peritoneal attachments on the inferior border of the pancreas are divided, and an assessment of the tumor location and anticipated pancreatic transection are noted. Care is taken to identify and preserve the inferior mesenteric vein as it enters the splenic vein posteriorly near or at the SMV–splenic vein junction. The splenic artery is identified on the superior aspect of the pancreas and traced back to its origin near the celiac trunk. The splenic artery is encircled and a test clamp applied to ensure that there is still adequate flow to the liver through the hepatic artery. Tumors in the body and neck region of the pancreas often track along the splenic artery, so it is important to ensure that a clear margin can be established at the takeoff from the celiac trunk. The artery is intentionally secured and divided first to reduce blood loss. The dissection of the pancreas is conducted from lateral to medial (releasing the splenic attachments and lifting the spleen up with the tail of the pancreas) or from medial to lateral by dividing the pancreatic parenchyma first.