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5 Pancreatic and Periampullary Carcinoma (Nonendocrine) CHAPTER 5 Pancreatic and Periampullary Carcinoma (Nonendocrine) TAYLOR A. SOHN • CHARLES J. YEO Ductal adenocarcinoma is the most common primary atic cancer, a risk approximately 30 to 40% higher than malignant disease of the pancreas and periampullary re- that observed in whites.2 gion. It accounts for more than 75% of all nonendocrine In population studies in the United States, pancreatic tumors arising in this region, which includes the pan- cancer occurs more frequently among Jews than among creas, the ampulla of Vater, the distal common bile duct, Roman Catholics or Protestants. A similar pattern is ob- and the perivaterian duodenum. Pancreatic adenocarci- served among Jews and non-Jews in Israel. Mormons in noma is the most common of the periampullary neo- Utah have been reported to have a lower incidence of plasms. In the United States, the annual incidence of pancreatic and other smoking-related cancers. However, pancreatic cancer is 9 cases per 100,000 population; this decrease is also seen in non-Mormons living in Utah, it ranks eleventh among all cancers and ninth among a finding suggesting that environmental factors may play nondermatologic cancers. It remains the most lethal can- a significant role. Some evidence indicates that migrant cer, with an overall 5-year survival rate of less than 3% and status is a risk factor. Immigrants from Japan have a a death-to-incidence ratio of approximately 0.99. Because threefold higher risk of developing pancreatic cancer more than 28,000 persons in the United States are ex- than do children born in the United States of Japanese pected to die of pancreatic cancer in 2000, it is the fifth immigrant parents and a 1.7-fold higher risk than whites leading cause of cancer deaths in this country.1 This in the United States.2 chapter largely focuses on pancreatic adenocarcinoma. From a worldwide perspective, pancreatic cancer rates Ampullary, distal common bile duct, and duodenal are highest in Western and industrialized countries and adenocarcinomas are less common than pancreatic tu- lowest in developing nations. An exception is noted in mors. They account for 15 to 20% of all periampullary the Maoris, a Polynesian people native to New Zealand, malignant diseases. Arising in the same region, they are who have incidence rates similar to those seen in devel- associated with similar clinical presentations and manage- oped countries.5 ment algorithms, but these tumors have different survival rates. These entities are discussed briefly in this chapter. Host Factors EPIDEMIOLOGY AND RISK FACTORS Host factors play an important role in the development of pancreatic cancer. The most striking examples are the six genetic syndromes associated with an increased risk Demographic Patterns of developing pancreatic cancer. These syndromes are hereditary nonpolyposis colorectal cancer (HNPCC), fa- The risk factors for pancreatic cancer have been well milial breast cancer associated with BRCA-2 mutations, studied and are summarized in Table 5–1. From 1920 to Peutz-Jeghers syndrome, ataxia-telangiectasia syndrome, 1978, the incidence rates of pancreatic cancer in the familial atypical multiple mole–melanoma syndrome United States increased nearly threefold, and they subse- (FAMMM), and hereditary pancreatitis. In addition to the quently have plateaued. In nearly all European countries, genetic syndromes, pancreatic cancer has been noted to a similar increase has been observed, with incidence rates aggregate in families. Evidence from the National Familial that continue to rise. A portion of this apparent increase Pancreas Tumor Registry (NFPTR) at the Johns Hopkins may have resulted from misclassification of pancreatic Hospital in Baltimore indicates that members of families cancers as other cancers, particularly gastric cancer, early with two or more first-degree relatives affected by pancre- in the 1900s. However, several subsequent analyses have atic cancer have at least a 16-fold increased risk of devel- indicated that part of the increase is real, despite con- oping pancreatic cancer. this finding could be accounted founding factors.2–4 for by a common nongenetic environmental exposure; Advancing age is a risk factor for pancreatic cancer, however, evidence suggests that this observed familial with 80% of cases occurring in patients 60 to 80 years of aggregation has some genetic basis.6 age. The gender distribution of pancreatic cancer has Chronic pancreatitis, which is most commonly related nearly equalized, and the incidence is slightly higher in to alcoholism, has been associated with an increased risk males. Blacks have the highest worldwide risk of pancre- of developing pancreatic cancer. Although several studies 5-5002 Volume III • Pancreas Table 5–1. Epidemiology and Risk Factors Increased Risk Possible Risk Unproven Risk Decreased Risk Demographic Factors: Advancing age Geography Socioeconomic status Black race Migrant status Male gender Jewish ethnicity Host Factors: Hereditary nonpolyposis colorectal cancer Diabetes Peptic ulcer surgery Tonsillectomy Familial breast cancer Chronic pancreatitis Cholecystectomy Allergic disorders Peutz-Jeghers syndrome Endocrine tumors Ataxia-telangiectasia Cystic fibrosis Familial atypical multiple-mole melanoma Sex hormones Hereditary pancreatitis Pernicious anemia Environmental Factors: Tobacco Diet Alcohol Occupation Coffee Radiation *From Gold, E.B., and Goldin, B.: Epidemiology of and risk factors for pancreatic cancer. Surg. Oncol. Clin. North Am., 7:67, 1998, with permission. demonstrate such an increased risk,2,7–9 others suggest Several reviews have examined the relationship of di- that an increased risk is observed only when the diagno- etary factors to the development of pancreatic can- sis of chronic pancreatitis precedes the diagnosis of can- cer.2,18,19 Despite conflicting data, some generalizations cer by less than 10 years.10 These data imply either a can be made. Pancreatic cancer appears to be associated common risk factor for the two diseases or the suggestion with increased total energy intake, as well as increased that chronic pancreatitis may represent an indolent pre- intake of carbohydrate, cholesterol, meat, salt, dehydrated sentation of pancreatic cancer. food, fried food, refined sugar, soybeans, and nitrosa- The data regarding the association of diabetes and mines. Fat, beta carotene, and coffee are of unproven pancreatic cancer are inconsistent. Most studies do not risk, whereas dietary fiber, vitamin C, fruits, vegetables, demonstrate an association of diabetes with pancreatic absence of preservatives, raw foods, pressure cooking, cancer, except when cases are included in which diabetes and microwave cooking may have a protective effect. was diagnosed 1 to 5 years before the patient developed Alcohol, coffee, and radiation exposure do not appear pancreatic cancer. Chow and colleagues11 demonstrated to be risk factors for the development of pancreatic an increased risk only in patients developing diabetes cancer despite conflicting reports. When controlling for after age 40, whereas LaVecchia and colleagues12 showed age, gender, smoking, socioeconomic status, and amount a decreased risk with increasing time after the diagnosis of alcohol consumed, three case-control studies from of diabetes. These data suggest that diabetes is likely an Europe failed to demonstrate an association between al- early symptom of pancreatic cancer rather than a caus- cohol and pancreatic cancer.2 Despite past reports of ative factor. These data are inconsistent with several other increased risk of pancreatic cancer with coffee consump- studies demonstrating an increased risk over time.13,14 tion,20,21 numerous subsequent reports have reported no Several other host factors have been associated with association between the two. On the basis of these data, pancreatic cancer. These include thyroid tumors, other if an association exists, it is likely weak. The pancreas benign endocrine tumors, and cystic fibrosis.15 Equivocal appears to be relatively insensitive to ionizing radiation, results have been obtained regarding the influence of sex as demonstrated by studies evaluating the survivors of hormones on the development of pancreatic cancer, but the bombings of Hiroshima and Nagasaki. These studies some authors report an association.2,16 In Sweden, perni- have shown no increased risk of pancreatic cancer.23,24 cious anemia has been associated with an increased risk.2 Inconclusive data link previous peptic ulcer surgery and cholecystectomy to pancreatic cancer.17 Risk Factors for Other Periampullary Cancers Environmental Factors Other periampullary cancers including distal common bile duct, ampullary, and duodenal cancers are less com- A large body of evidence links cigarette smoking to pan- mon and therefore are less well characterized in terms of creatic cancer. Nitrosamines and tobacco smoke have risk factors. All are associated with increased age, with been shown to be carcinogenic for the pancreas in animal peak incidences in the 60- to 80-year range. Distal com- studies. In addition, human autopsy studies reveal hyper- mon bile duct cancers are associated with several known plastic changes with atypical nuclear patterns in the pan- host factors in addition to advanced age. These include creatic ductal cells of smokers. Several prospective stud- inflammatory bowel disease, sclerosing cholangitis, ies evaluating death from pancreatic cancer in smokers choledochal cysts, and intrahepatic or common bile duct have demonstrated increased risk ratios ranging
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