Cancers of the gallbladder, extrahepatic bile duct, and ampulla of Vater have distinct demographic patterns and should be described as distinct disease entities (7). Cancer of or near the ampulla of Vater (ampullary cancer) arises from the region of the small bowel where the main pancreatic duct and the common bile duct unite and exit the duodenal wall (8). More than 50% of malignant duodenal lesions are found in this area. Although ampullary cancer is sometimes grouped with malignancies of pancreatic origin, this tumor type has several features that distinguish it from pancreatic adenocarcinoma, most notably a better prognosis (9,10). Ampullary cancer is the least common of the biliary tree tumors and has a worldwide distribution. Its risk profile is to some degree independent of the other biliary tumors, as evidenced by the low rates of ampullary cancer in populations with traditionally very high rates of gallbladder cancer, such as the Australian Maori (10). Geographic clustering of ampullary cancer has been reported in at least one study from Japan (11).

Primary cancers of the bile ducts (cholangiocarcinomas) may arise from the epithelial lining of either the intrahepatic or the extrahepatic bile ducts (12). Carcinoma of the gallbladder also primarily arises from the gallbladder epithelium, although other histologic types with varying geographic distributions and survival outcomes (e.g., cystadenocarcinoma, squamous cell carcinoma, papillary carcinoma) also exist. Both cholangiocarcinoma and gallbladder cancer demonstrate wide geographic variation in frequency, suggesting environmental causes as one potential factor in their etiology. For example, incidence rates of these two tumors show remarkable regional variation in Asia, with some of the greatest extremes seen in Thailand and China. A comparison of the annual incidence rates for gallbladder cancer in international cancer registries shows differences of up to a factor of 25 (13). At least part of the geographic differences in gallbladder cancer, more so than cholangiocarcinoma, may relate to variation in the prevalence of gallstones in different ethnic groups (14).

Gallbladder cancer is rare in most Caucasian populations but is among the most frequently observed cancers in the native populations of North and South America and in the Maori of New Zealand. High rates are seen in the cancer registries of South American countries, such as Colombia; Eastern European countries, such as Poland and Hungary; and Israel (especially among Jews of European origin), where rates as high as 13.8 per 100,000 for women and 7.5 per 100,000 for men have been reported (15). Low rates are seen in the Middle and Far East, except in some high-risk areas; in the United Kingdom; and in the United States. Many regions of the world have reported declining rates of gallbladder cancer in recent years, including much of South America, Canada, Europe, and Poland. In China, where significant differences in incidence between mountain areas and flatlands have been previously reported (16), changes in gallbladder cancer incidence have been mixed, with Tianjin and Shanghai reporting increases, and Hong Kong decreases (17) (Table 34.1).

Within the United States, biliary tree cancers remain an exceedingly rare diagnosis, with <10,000 new cases reported per
year (2). Extrahepatic cholangiocarcinoma incidence has been decreasing in recent years (18), whereas intrahepatic cancers, more commonly found in peoples of Asian decent, have been increasing in the United States and other Western nations (12). Gallbladder cancer rates are high among Native Americans, in whom the overall rate of cancer is low, and in the Mexican American population (19). Recent data from the National Cancer Institute Surveillance, Epidemiology, and End Result (SEER) program shows more than threefold higher rates of gallbladder cancer among Native American/Alaskan Native males than among Caucasian or African American counterparts (20). These rates closely parallel those of gallstone disease.

Ampullary carcinoma is approximately 1.4 to 1.5 times more common in men than in women (9). This ratio is similar for cholangiocarcinoma (20). Carcinoma of the gallbladder in contradistinction is one of the few forms of cancer that does not arise in a gender-specific organ but that nonetheless occurs more commonly in women than in men (2,17,20). The female-to-male ratio in the United States is approximately 1.7 to 1 across all races, with higher female-to-male ratios seen in Native American/Alaskan Native (2.0–1) and Hispanic subgroups (1.9–1) (2,20).

Cancers of the biliary tree are primarily diseases of the elderly. Diagnosis and mortality for all types of biliary tract cancer are closely associated with age (2,4). The incidence of ampullary cancer and cholangiocarcinoma increases with age, with a mean age of diagnosis of approximately 63 years and 65 years, respectively (19). The trend of increasing incidence of intrahepatic cholangiocarcinoma appears to be greatest in older individuals (12). Like other epithelial cancers, gallbladder cancer rates also increase with age. The mean age at diagnosis of gallbladder carcinoma is 65 years (19).

Ampullary cancers have been described in a variety of racial and ethnic subgroups, but no studies have specifically examined the association of race with the incidence of this tumor. The rate of cholangiocarcinoma in Caucasian Americans is about 1.3 times that in African Americans. In particular, rates in Caucasian women and African American men appear to be increasing (20). Age-adjusted incidence rates of intrahepatic cholangiocarcinoma are equal among Caucasians and African Americans, whereas overall rates of extrahepatic cholangiocarcinoma are lower for African Americans (12).

In the United States, racial/ethnic groups with higher incidence rates of cholelithiasis, such as Native Americans and Hispanic Americans, have a higher incidence rate of gallbladder cancer as well. These data may reflect either environmental or genetic differences among the populations studied. In a case-control study of 131 patients with gallbladder cancer and 2,399 subjects without gallbladder cancer from three racial groups—Caucasian, African American, and southwestern Native American (14)—a significant relationship was seen between gallstones and gallbladder cancer. The overall estimated relative risk (RR) was 4.4 (95% confidence interval [CI], 2.6–7.3), but the estimated RR was much higher for the Native American group at 20.9 (95% CI, 8.1–54).

Updated incidence rates (per 100,000) published by the SEER program are shown in Table 34.2. Hispanic Americans have a high risk of developing carcinoma of the gallbladder (5,21), but this is not true for all Hispanic Americans. For example, in New Mexico, Texas, and California, where the ancestry of this group comprises European Spanish and Native
Americans, the risk of gallbladder cancer is higher (22). Other Hispanic groups, such as Cubans and Puerto Ricans, have gallbladder cancer incidence rates no different from those of the general U.S. population (23).

Temporal changes in incidence have been observed for the biliary tree tumors. A recent 20-year population-based series (1976–1995) reported an increasing incidence of ampullary cancer in France (9). Based on SEER data, the incidence of cholangiocarcinoma has also steadily increased over the past 20 years in the United States and may be secondary to increases in intrahepatic cholangiocarcinoma (12). Overall gallbladder cancer incidence and mortality rates have continued to decrease in the United States, although rates in black females have slowly trended upward (7).

Changes in the management of benign biliary disease may impact cancer rates. Benign gallbladder disease increases the risk of cancer in all regions of the biliary tract (24,25). Cholecystectomy is now frequently undertaken for benign gallbladder disease, in part as a prophylactic measure against subsequent malignancy. This has become more widespread with the use of laparoscopic cholecystectomy, and increases in cholecystectomy rates in the United States have been documented (26,27). This is one possible explanation for the reduced mortality from gallbladder cancer that has been observed in the United States and Europe (28). In a more recent Italian series, only 20% of gallbladder cancers identified histologically after laparoscopic cholecystectomy were suspected preoperatively or intraoperatively, indicating that many gallbladder tumors are likely removed serendipitously (29). Interestingly, the risk of cholangiocarcinoma is also reduced after cholecystectomy (30).

Gallbladder carcinoma has been shown to be strongly associated with cholelithiasis. Numerous studies have shown an increased risk of gallbladder cancer in individuals with cholelithiasis (31,32,33). Gallstones are found in up to 90% of patients with gallbladder cancer (33). It is not clear whether there is a causal relationship between gallstones and the development of carcinoma of the gallbladder or whether the two conditions share similar risk factors. The epidemiology of cholelithiasis runs parallel to that of gallbladder cancer. The highest incidence of gallbladder cancer is seen in those areas with the highest prevalence of gallstones, especially in the indigenous populations of Chile, Bolivia, Ecuador, Mexico, and Native Americans of the southwestern United States (34). It has been hypothesized that inflammation due to the presence of gallstones probably contributes to the stepwise progression from epithelial dysplasia to carcinoma in situ to invasive carcinoma of the gallbladder (35).

Patients with gallstones have been shown to have an increased risk of gallbladder cancer. A hospital-based case-control study, with a review of medical records of 69 patients with primary biliary tract cancer, found a significant association between cholelithiasis and biliary tract cancers (odds ratio [OR], 19.5; 95% CI, 6.4–59.4) (36). A multicenter case-control study by Zatonski et al. (37) found that patients with gallbladder cancer had an OR of 4.4 (95% CI, 2.6–7.5) for having a history of symptomatic cholelithiasis or choledocholithiasis. In addition, studies of patients undergoing cholecystectomy for cholelithiasis have shown a postoperative incidental finding of gallbladder cancer in 0.3% to 3% of cases (38,39,40). Larger gallstones appear to correlate with an increased risk of gallbladder cancer as compared to smaller stones. A study by Diehl (41) demonstrated an odds ratio of 10.1 (95% CI, 2.6–39.7) for the development of gallbladder cancer in individuals with gallstones >3.0 cm in diameter. A cross-sectional study of 1,676 patients undergoing cholecystectomy calculated an odds ratio of 9.2 (95% CI, 2.3–37) for gallbladder cancer in subjects with gallstones >3 cm compared to subjects with gallstones <1 cm in diameter (42).

Although the evidence is limited, there may also be an association between cholelithiasis and increased risk of cholangiocarcinoma. A retrospective review from two hospitals in Taiwan showed that up to 67% of patients with cholangiocarcinoma had a history of cholelithiasis (43). The presence of intrahepatic stones has also been observed in 5.7% to 17.5% of cholangiocarcinoma cases in a Japanese series (44). In such instances, the bile duct epithelium generally shows chronic proliferative cholangitis and epithelial hyperplasia (45).

In approximately 1% of patients who undergo cholecystectomy for cholecystitis, an undiagnosed gallbladder cancer is present. In a single center retrospective review of 80 patients older than 60 years who were admitted with acute cholecystitis, 0.9% were found to have gallbladder cancer (46). Premalignant changes include epithelial hyperplasia, dysplasia, and frank carcinoma. These changes have been identified in 13.5%, 8.3%, and 3.5%, respectively, of patients undergoing cholecystectomy for cholelithiasis or cholecystitis (47). In a Japanese series,
14% of patients who underwent cholecystectomy for chronic cholecystitis had evidence of either severe dysplasia or carcinoma in situ (48).

Patients with long-standing cholecystitis can develop calcification of the gallbladder wall, a condition known as porcelain gallbladder. Several older series have demonstrated a strong association between porcelain gallbladder and gallbladder cancer, with a cumulative incidence ranging between 12.5% and 61.0% (49,50). A more recent retrospective review, however, failed to identify any cases of carcinoma in patients with porcelain gallbladder (51).

Cholangiocarcinoma, both intrahepatic and extrahepatic, has been reported as a complication of sclerosing cholangitis. Lifetime risks of developing carcinoma have been reported as between 10% and 30%, although the majority of reports estimate a risk closer to 10% (52,53,54). Undiagnosed cholangiocarcinoma in association with primary sclerosing cholangitis (PSC) has been found at the time of orthotopic liver transplantation (55,56). The time from diagnosis of PSC to the development of cholangiocarcinoma ranges from 1 to 25 years, with more than one-third of the cases being detected within 2 years of the initial diagnosis (53,57). This short interval is likely due to the lack of symptoms associated with early PSC. There may be an increased risk of gallbladder cancer in patients with PSC. In a series of 121 patients with PSC, 3 were found to have gallbladder cancer (58). Whether the observed cases were related to PSC itself or to the presence of gallstones is unclear.

Secondary sclerosing cholangitis, which clinically mimics PSC, is due to an underlying insult, such as chronic biliary obstruction due to stones or ischemic biliary strictures. Individuals with this condition also can progress to cirrhosis. Although the natural history of secondary sclerosing cholangitis is not fully known, there have not been any reports to date of cholangiocarcinoma developing in the setting of secondary sclerosing cholangitis (59).

Bile duct carcinoma has been documented as a complication of inflammatory bowel disease, albeit much less frequently than carcinomas affecting the colon. This may be in part due to the strong association between PSC and ulcerative colitis, and the presence of serum antibodies in patients with both conditions that cross-react with bile ducts (60,61). The incidence of bile duct cancer was 1 in 246 patients with ulcerative colitis in one series (62), with one-fifth of cases occurring in intrahepatic bile ducts, and 2 in 200 patients at The Johns Hopkins Hospital (63). In a series at the Mayo Clinic, the average age at diagnosis of bile duct cancer for patients with ulcerative colitis was 38 years and occurred at a mean follow-up of 19 years after the diagnosis of ulcerative colitis (64). The risk of bile duct cancer does not appear to be affected by proctocolectomy (63).

Benign neoplasms of the extrahepatic bile ducts are relatively uncommon. In a histopathological study of 43 cases of carcinoma of the extrahepatic ducts, adenomatous residue was found in 9 cases (21.4%). This frequency was comparable to that seen in carcinoma of the colon and rectum (65), in which most carcinomas arise from preexisting adenomas. The frequency of preexisting adenomas was also similar for carcinoma of the gallbladder (66), and in the ampulla of Vater, adenomatous residue was found in 18 or 22 carcinomas (81.8%) (67).

Adenomatous gallbladder polyps are a predisposing factor for the development of carcinoma and gallbladder polyps are not uncommon. Malignant polyps tend to be found in older patients and in individuals with larger polyps. In a study from Japan, 194,767 subjects had an abdominal ultrasound as part of routine health screening. The prevalence of gallbladder polyps in this population was 5.6%. In addition, the presence of polyps ≥1 cm in diameter was found to be associated with a significantly increased risk of gallbladder cancer (68). In a retrospective study of 100 patients who underwent cholecystectomy and were found to have polypoid lesions of the gallbladder, 73% of the patients with malignant polyps were older than 60 years, and 88% of the malignant polyps were ≥1 cm in diameter (69). Small polyps (<1 cm) are unlikely to be malignant. In a study evaluating gallstone prevalence by ultrasound in diabetics and matched controls, 6.7% of the diabetics were found to have gallbladder polyps. More than 90% of these polyps were <1 cm in diameter, and very few of these polyps changed in size over the 5-year follow-up period (70). It appears that patients with PSC have a much higher risk of malignant gallbladder polyps. Buckles et al. (71) performed a retrospective case series from the Mayo Clinic and found that, in patients with PSC who underwent cholecystectomy for polypoid lesions of the gallbladder, 57% of the gallbladders had adenocarcinoma, and one-third of the benign gallbladder lesions had associated epithelial cell dysplasia.

Patients with familial adenomatous polyposis (FAP) have a risk of ampullary adenocarcinoma that is estimated to be 100 times that of the general population (72). An association is also found between adenomatous polyps of the gallbladder seen with Peutz-Jeghers syndrome (PJS) and gallbladder cancer (73,74).

Patients with choledochal cysts have an increased incidence of both gallbladder and bile duct carcinoma. Choledochal cysts are preexisting lesions that is present in 9–24% of bile duct cancers. Cholangiocarcinomas in the presence of choledochal cysts tend to develop at an earlier age than sporadic cholangiocarcinoma (75,76). The incidence of cholangiocarcinoma in individuals with choledochal cysts increases with age, and the mean age of diagnosis of cholangiocarcinoma is in the fourth decade of life (77). Premalignant changes, such as epithelial metaplasia, are also seen with increasing frequency with older age in these cysts (78). Choledochal cysts are more prevalent in females (4:1) and in Asia (79). The Todani classification system (75) is used to differentiate these cysts on an anatomical basis. Type I cysts (fusiform dilation of the extrahepatic duct) and type IV cysts (combined intra- and extrahepatic dilation or multiple extrahepatic dilations) have the highest risk of malignant transformation (80). Although the majority of cancers arise from within the cysts, malignant transformation can occur anywhere in the biliary tree.

Gallbladder cancer has also been seen in the setting of an anomalous junction of the pancreaticobiliary duct (AJPD) (15), at times in association with a choledochal cyst (81). A study of 1,876 consecutive patients in China who underwent endoscopic retrograde cholangiopancreatography (ERCP), 10 patients were identified as having AJPD, and 7 of these had gallbladder cancer. The odds ratio for having AJPD in patients with gallbladder cancer in that study was 50.7 (95% CI, 12.7–202.3) (82). In another study of 126 patients with gallbladder cancer who had previously undergone
cholangiography, the prevalence of AJDP was 18% (83). Whether the increased risk of cancer is a result of the anomalous junction and subsequent bile stasis and carcinogen retention within the biliary tree, the regurgitation of pancreatic juice or chronic inflammation is unclear.

The incidence of biliary tract cancer is increased after partial gastrectomy. This may relate to the increased occurrence of gallstones after gastrectomy (84). In a prospective study of 48 gastric cancer patients who underwent partial or total gastrectomy, 18% subsequently went on to develop gallstones (85). After distal gastrectomy, patients have prolonged gallbladder bile emptying into the duodenum (86). Alternatively, the increased risk of biliary cancer may be due to the presence of N-nitroso compounds that are formed in the gastric remnant after partial gastrectomy (87). In a study evaluating risk factors for the development of gallstones after gastrectomy, total gastrectomy (vs. partial), reconstruction with duodenal exclusion (vs. nonexclusion), and lymph node dissection in the hepatoduodenal ligament were all identified as risk factors for the subsequent development of gallstones (88).