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Pancreatic and Periampullary Cancer
Pancreatic and periampullary tumors include a diverse group of malignant neoplasms that arise in the pancreas or at or near the ampulla of Vater. These neoplasms commonly include adenocarcinomas of the pancreas (pancreatic ductal adenocarcinomas [PDACs]), duodenum, distant common bile duct, or ampulla of Vater in addition to pancreatic neuroendocrine tumors (PNETs). Other neoplasms located in this region include intraductal papillary mucinous neoplasms (IPMNs), acinar cell cancer, mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). Presentation of these tumors is often similar given their common location of origin with symptoms including abdominal discomfort, obstructive jaundice and pruritus for lesions located in the head of the pancreas or periampullary region, and pain or abdominal discomfort for pancreatic tail lesions. The surgical management of these neoplasms is often similar given their shared location, but differences in underlying biology can dictate subtle differences in care requiring the need for accurate diagnosis and differentiation of these neoplasms.
Incidence
The most common periampullary malignancy is PDAC, followed by ampullary adenocarcinoma, distal cholangiocarcinoma, and duodenal adenocarcinoma. Other, less common lesions can also be found in this region, including PNETs, acinar cell cancer, IPMNs, sarcomas, gastrointestinal (GI) stromal tumors, MCNs, SPNs, and metastases from other cancers. Although periampullary cancers are generally less common compared to other malignancies including colorectal, breast, and lung, they remain a major cause of mortality often related to their difficulty to diagnose early. An estimated 53,000 cases of pancreatic adenocarcinoma are estimated for 2016, making it the ninth most common cancer in the United States. However, approximately 42,000 deaths due to PDAC are expected for the same time period, making it the fourth leading cause of cancer death with a 5-year overall survival of only 7%. The number of new cases of pancreatic cancer in the United States is approximately 10 to 12 per 100,000 men and women per year, which has remained relatively steady over the past several decades. A similar, stable incidence has been seen in European nations over the past several decades. A dramatic increase has been seen in pancreatic cancer rates in Japan over the past 3 decades, although the overall incidence of PDAC in Japan, the Middle East, and Asia remains lower than in Western nations.
Cholangiocarcinoma is a tumor of the bile ducts found along the biliary tree and occurs less frequently than pancreatic adenocarcinoma. Distal bile duct carcinoma comprises 20% to 40% of all cholangiocarcinomas. The exact incidence and death rate is difficult to ascertain because distal cholangiocarcinomas are usually combined with other cholangiocarcinomas (hilar and intrahepatic) and gallbladder cancer cases when the annual incidence is reported. The overall incidence of extrahepatic cholangiocarcinoma has been suggested at 1 case per 100,000 individuals in the United States, with a higher incidence in Western countries compared with Asian and Eastern countries.
Ampullary adenocarcinoma is a rare tumor arising from the ampulla of Vater that accounts for 6% to 19% of periampullary cancers. Although uncommon, its incidence is estimated at 6 cases per 1 million individuals and has been slowly rising over the past 3 decades. In addition, compared to other periampullary malignancies, ampullary cancers tend to become symptomatic at an earlier stage and thus as many as 80% of these tumors are resectable. Duodenal adenocarcinoma of the periampullary region is the least common of the main periampullary cancers. It is often difficult to estimate the exact incidence of these tumors because duodenal cancers are combined with other malignancies of the small bowel when reporting overall statistics.
Pathology
Pathologic examination of the surgical specimen after pancreaticoduodenectomy (PD) reveals a disease breakdown with a pattern similar to the overall incidence. The majority (40% to 60%) of resections are for pancreatic adenocarcinoma, 10% to 20% for ampullary adenocarcinoma, 10% for distal cholangiocarcinoma, 5% to 10% for duodenal adenocarcinoma, and 10% to 20% for benign disease. However, it is important to note that this breakdown only involves resectable tumors. Only a minority of patients who present with pancreatic adenocarcinoma are found to have a resectable tumor without distant metastases, and as such it is likely that the incidence of pancreatic adenocarcinoma making up periampullary tumors is much higher than reported.
Most pancreatic adenocarcinomas arise from the head, neck, or uncinate process and are the predominant tumor pathology seen in this region. In addition, rare tumor variants exist for pancreatic adenocarcinoma, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma (mucinous noncystic), and medullary carcinoma. Each variant has distinct pathologic findings different from the traditional pancreatic adenocarcinoma, often leading to differences in survival following resection. Other less common tumor types in the pancreas include acinar cell cancer, PNETs, MCNs, and SPNs.
Cystic neoplasms of the pancreas have been more frequently identified in recent years, likely due to the increasing use of cross-sectional imaging. The majority of these lesions are benign with little malignant potential, such as serous cystadenomas, whereas others such as IPMNs are of keen interest given their identification as precursors to the development of invasive ductal adenocarcinoma. Noninvasive IPMNs are classified based on their degree of dysplasia into three groups—low grade, intermediate grade, or high grade—although recent discussion has suggested simply categorizing all noninvasive IPMNs as either low/intermediate grade or high grade. In addition, histologic subtypes of IPMNs exist including pancreatobiliary type, gastric type, intestinal type, and oncocytic type, with slightly differing natural histories based on each type. Institutional studies of IPMNs have demonstrated a rate of associated invasive cancer at the time of resection between 30% and 38%. Data are equivocal, however, as to whether invasive adenocarcinoma derived from an IPMN possesses improved overall survival when compared to traditional PDAC.
Similar precursors of the biliary tree known as intraductal papillary neoplasms of the biliary tract (IPNBs) have also been identified in recent years. Analogous to IPMNs, these are also characterized by different histologic subtypes (pancreaticobiliary, intestinal, gastric, and oncocytic), identified based upon histopathologic analysis of cells present and by immunologic staining by cytokeratins and mucin markers. IPNBs are believed to be precursor lesions to the development of cholangiocarcinoma, much like the progression of an IPMN to PDAC. One series of 343 patients found that 11% ( n = 39) of patients had IPNB by histology after resection of a bile duct tumor, with 29 of 39 patients (74%) having an invasive carcinoma component in association with the IPNB.
Rare causes of periampullary tumors include metastatic disease from the kidney, lung, melanoma, breast, colon, stomach, or tumors from other primary sites of disease. Sarcomas, including gastrointestinal stromal tumors (GISTs), leiomyosarcoma, histiocytomas, and fibrosarcomas, may also arise in the periampullary region. Differentiation among these different sarcoma types is important in terms of management, as GISTs are highly responsive to targeted immunotherapies such as imatinib mesylate (Gleevec). Lymphomas have also been seen in the periampullary region given the presence of large areas of lymphatic tissue around the pancreas and porta hepatis.
Risk Factors
Pancreatic Adenocarcinoma
The risk factors for pancreatic adenocarcinoma are the best documented of all the periampullary tumors, although our understanding of them remains incomplete. These risk factors include advanced age, diabetes mellitus, obesity, African American race, a current or prior history of tobacco use, chronic pancreatitis, and family history/genetics. Most cases of PDAC occur in adults older than 50 years, with pancreatic cancer rarely seen under the age of 40 years. Smoking confers an increased risk of developing PDAC compared to nonsmokers (odds ratio [OR] 1.71), and former smokers who had quit for less than 5 years were also shown to have a higher risk of developing PDAC (OR 1.78). A family history of pancreatic cancer, especially when two or more first-degree relatives are affected, is considered a strong predictor of developing PDAC. Other factors such as alcohol consumption, coffee consumption, prior cholecystectomy, physical inactivity, and a dietary intake of meat and sugar have been suggested to confer an increased risk of PDAC, but these are unlikely to be true risk factors.
Several genetic syndromes and risk factors have been associated with an increased risk of developing pancreatic cancer. However, familial clustering accounts for only 5% to 10% of pancreatic cancer cases. Large population studies have shown an overall risk of 1.8 to 2.3 for the development of PDAC in individuals with an affected first-degree relative. This risk increases to 6.4-fold with two first-degree affected relatives, and three first-degree relatives with PDAC confers a 32-fold increased risk of an individual developing pancreatic cancer. Individuals with BRCA1 and BRCA2 mutations are at a higher risk of developing pancreatic tumors, with a risk of 3.5- to 10-fold in BRCA2 mutation carriers. Germline BRCA2 mutations are also associated with an increased risk of breast, prostate, and ovarian cancer. Peutz-Jeghers syndrome, defined by STK11/LKB1 mutations, is a rare autosomal dominant disorder marked by the development of benign hamartomatous polyps in the GI tract and small, dark-colored macules in and around the mouth. Individuals with this disorder carry a 132-fold increased risk of developing PDAC. Familial atypical multiple mole melanoma (FAMMM syndrome) involving mutations in CDKN2A leads to the development of multiple atypical nevi and an increased risk of melanoma, and can confer an almost 22-fold increased risk of pancreatic cancer. Other genetic risk factors include familial adenomatous polyposis (FAP) (APC mutations) with a 4.5-fold increased risk, Lynch syndrome (MSH2, MLH1/HNPCC mutations) with an 8.6-fold increased risk of PDAC, and hereditary pancreatitis (PRSS1 mutations) with a 53-fold increased risk of pancreatic cancer for affected individuals.
Somatic Genetic Alterations and Pancreatic Cancer
A high level of detail regarding the global genetic landscape (i.e., cancer genome) is known for pancreatic cancer as the result of several recent publications on this subject. A comprehensive analysis of pancreatic tumors from 24 individuals identified a core set of 12 signaling pathways that were genetically altered in 67% to 100% of the tumors studied. These mutations allow the cancer to evade apoptosis, grow unconstrained, and metastasize to distant organs. All tumors studied were found to have mutations in the KRAS, Wnt/Notch, TGF-β, and hedgehog (Hh) signaling genes, whereas most cancers sampled have mutations in processes that regulate invasion or involve DNA damage control (p53). Overall, an average of 63 mutations were found per individual tumor indicating heterogeneity among most pancreatic tumors despite a core of common mutations. In addition, a comparison of mutations in key pathways such as KRAS, SMAD4, and p53 found a similar rate of mutations in these genes among both familial and sporadic pancreatic cancer cases.
A larger analysis of 100 pancreatic tumors by whole-genome sequencing recently confirmed the presence of many common mutational pathways (KRAS, SMAD4, TP53, CDKN2A, and MAP2K4) while further demonstrating that tumors could be categorized into four subtypes based on the mutations observed: stable, scattered, unstable, and locally rearranged. The stable subtype (20%) contained less than 50 structural variation events, suggesting defects in the cell cycle and mitosis with similar point mutations seen for KRAS and SMAD4 . The locally rearranged subtype (30%) involved a significant focal event on one or two chromosomes, either involving focal regions of copy number gain or complex genomic rearrangements. The scattered subtype (36%) involved tumors with a moderate range of nonrandom chromosomal damage. The least common type of tumor seen was the unstable subtype (14%), which involved tumors with a large number of structural variation events suggesting defects in DNA maintenance. This work suggested that the different subtypes could aid in the understanding of the underlying tumor and offer potential stratification methods for therapeutic intervention.
Genomic data have also suggested a large window of time in which these mutations accumulate and lead to the development of a clinically evident pancreatic tumor. Sequencing of cancer cells from primary and metastatic pancreatic tumors involving data on the accumulation of mutations estimates an average of 11.7 years from tumor initiation to the development of a clinically visible primary pancreatic tumor, with an additional 6.8 years to the development of metastatic disease. This suggests that a large window of time is needed for mutations to occur and tumors to develop, and offers a potentially long window for future screening programs.
Other Periampullary Tumors
Risk factors for the remaining periampullary tumors (duodenal, ampullary, and distal cholangiocarcinoma) are often related to genetic or environmental factors, but these are less well understood than pancreatic tumors. Similar to pancreatic adenocarcinoma, most periampullary cancers are seen in patients of advanced age with the tumors rarely occurring before the age of 50 years. A higher risk of developing cholangiocarcinoma has been seen in association with primary sclerosing cholangitis (PSC), choledochal cysts, choledocholithiasis, inflammatory bowel disease, and infections including liver flukes ( Clonorchis sinensis , 4.8-fold risk), hepatitis B (OR 2.6), and hepatitis C (OR 1.8). Ampullary carcinoma is increasingly seen in patients with hereditary polyposis syndromes including hereditary nonpolyposis colorectal cancer (HNPCC), Peutz-Jegher syndrome, and FAP.
Diagnosis
Clinical Findings
Pancreatic and periampullary malignancies are often difficult to diagnose early given a paucity of specific clinical findings. Many patients, especially those with small tumors and early-stage disease, will be asymptomatic. Furthermore, exact symptoms are vague and depend on the location of the lesion. The most common presenting symptom for periampullary tumors is jaundice caused by biliary outflow obstruction, classically referred to as “painless jaundice.” Often, biliary obstruction will be associated with dark urine, pruritus, scleral icterus, and light-colored stools. Additional symptoms of weight loss, fatigue, and mild epigastric pain or discomfort radiating to the back may be present, and nausea and vomiting may be seen in those with duodenal obstruction. Conversely, patients with tumors of the body or tail of the pancreas more commonly present with weight loss, nausea, early satiety, and epigastric pain. Patients with extensive disease burden or tumor invasion into the celiac nerve plexus may present with severe abdominal pain, although this is not common. Rare symptoms of periampullary and pancreatic neoplasms include acute pancreatitis, upper GI bleeding, and cholangitis.
A complete history and physical should be performed for any patient presenting with concern for a pancreatic or periampullary neoplasm, with special focus on any potential risk factors or a family history of malignancy. Physical examination is often nonspecific but may include jaundice, scleral icterus, abdominal discomfort, hepatomegaly, or a palpable gallbladder (Courvoisier sign). Palpation of a periumbilical nodule (Sister Mary Joseph nodule), left supraclavicular node (Virchow node), or pelvic nodules felt on rectal examination (Blumer shelf nodule) may be present in patients with advanced periampullary tumors.
Laboratory findings may be subtle in patients with periampullary tumors. Mildly elevated transaminases, alkaline phosphatase, and bilirubin levels may be seen, and can become severely elevated in those patients with obstructive jaundice. Coagulopathy may be seen in association with biliary obstruction due to vitamin K deficiency, whereas the combination of malnutrition and weight loss can lead to anemia and hypoalbuminemia. New-onset diabetes with an elevated fasting glucose precedes the diagnosis of periampullary tumors in some with pancreatic cancer. Tumor markers should be sent including carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). Although CA 19-9 levels are elevated in most patients with pancreatic and periampullary cancers, it has limited diagnostic capabilities given similar elevations seen in patients with benign pancreas and biliary diseases. However, baseline CA 19-9 levels are important to obtain and trend to allow monitoring for tumor recurrence or evaluating therapy response.
Imaging Studies
Pancreatic and periampullary tumors are most frequently diagnosed through a combination of imaging modalities including right upper quadrant ultrasound (RUQ US), computed tomography (CT) scans, magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP), and percutaneous transhepatic cholangiography (PTC). An RUQ US may be the first imaging obtained to work up a patient with abdominal pain or biliary symptoms, and may show a dilated biliary tree, gallstones, or gallbladder distention. Hepatic metastases and ascites suggestive of advanced disease may also be seen by ultrasound. However, this modality is not sensitive for demonstrating a pancreatic or periampullary mass, and additional imaging is needed to sufficiently rule out a tumor in this region.
High-quality cross-sectional imaging is imperative for the detection of a periampullary tumor, assessment of resectability, and the evaluation of metastatic disease. In the majority of patients, periampullary tumors are first identified by CT scan obtained due to vague abdominal complaints or identified incidentally when the patient undergoes imaging for an unrelated etiology. Multidetector computed tomography (MDCT) scans remain the most useful initial imaging modality and provide a highly sensitive way to identify periampullary tumors and their relationship to nearby structures ( Fig. 96.1 ). Three-dimensional reconstruction of the vasculature aids in determining the relationship between the mass and important blood vessels, namely the superior mesenteric artery, celiac artery axis, superior mesenteric vein, and portal vein. MDCT has a sensitivity as high as 90% for evaluating vascular involvement of pancreatic tumors and distal cholangiocarcinoma. Furthermore, MDCT has the capability to detect liver metastases with a relatively high sensitivity, although this is dependent on the size of the lesion. Together, MDCT can aid in the diagnosis of periampullary tumors, assessing for resectability, and determining alternative treatment methods in patients with vascular invasion, local advancement, or distant disease ( Fig. 96.2 ).
MRI is rarely the first imaging modality used for the diagnosis of periampullary tumors, but is often obtained in conjunction with an MDCT scan to better delineate periampullary tumors. This is typically the case when distal biliary obstruction is present or suspected but no discrete mass can be seen on CT scan. MRI and MRCP are especially useful in the detection of distal bile duct tumors, allowing for easier identification of a tumor's extent and visualization of the bile and pancreatic ducts ( Fig. 96.3A and B ). Often, a tumor of the bile ducts will be identified on MRI or MRCP by thickening or irregularity of the bile duct wall with proximal dilatation of the biliary tree. MRCP, especially, is a noninvasive method to assess the bile ducts without the risk of invasive cholangiopancreatography but has been shown to be equivalent to ERCP in the diagnosis of cholangiocarcinoma. However, if an intervention such as stent placement or tissue diagnosis is required, ERCP is still necessary.
EUS and ERCP provide useful adjuncts to cross-sectional imaging for the diagnosis of periampullary tumors. These methods provide a method to diagnose a suspected pancreatic or periampullary tumor while also obtaining tissue for pathologic diagnosis. EUS provides direct visualization of ampullary and duodenal cancers with a relatively easy way to obtain tissue for pathologic diagnosis. EUS can also provide information on the location and size of a pancreatic lesion in addition to nodal staging and information on vascular invasion. Fine-needle aspiration can be added to EUS to provide tissue diagnosis prior to surgical resection or neoadjuvant therapies in situations where a definitive diagnosis is unclear. On ERCP, pancreatic cancers will classically demonstrate a long, irregular stricture in the pancreatic duct with distal dilation of both the pancreatic and distal bile ducts ( Fig. 96.4 ). Furthermore, ERCP can be utilized to decompress an obstructive biliary tree with stent placement while obtaining bile duct brushings, thus alleviating jaundice and obtaining a tissue diagnosis. However, routine ERCP and stenting is not advised on all patients with pancreatic or periampullary tumors given the potential increase in wound infections after surgery and associated complications such as post-ERCP pancreatitis.
PTC is an additional method used to define the biliary anatomy. However, given its invasive nature, it is usually reserved for instances when endoscopic decompression is not possible. Tissue biopsies can be performed at the time of cholangiography, and a drainage catheter can be inserted to allow for decompression of the biliary tree when ERCP has failed. PTC has been shown to have a similar sensitivity and specificity when compared to ERCP for obtaining a tissue diagnosis for cholangiocarcinoma. However, PTC is associated with more severe complications such as hemobilia when compared to EUS or ERCP, often due to its more invasive nature.
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