Gallbladder cancer is the most frequent carcinoma of the biliary tract and the fifth most frequent carcinoma of the alimentary tract. The overall 5-year survival rate is less than 5 per cent, and the overall 1-year survival rate is less than 12 per cent. Gallbladder carcinoma is detected in about 2 per cent of patients undergoing gallbladder and biliary surgery. Because of the enhancing effect of female sex hormones on the formation of gallstones, women have more and larger stones than men, and there is a female : male ratio of 4 : 1 among patients with gallbladder carcinoma.

A direct association exists between the presence of cholelithiasis and the pathogenesis of gallbladder cancer. In patients with gallbladder carcinoma, the incidence of cholelithiasis ranges from 54 to 97 per cent. The incidence of gallbladder cancer increases with age, especially in women with cholelithiasis. The incidence of gallbladder cancer is 0.03 per cent in women under the age of 50 with gallstones, 3.8 per cent those over the age of 50, and 8.8 per cent in those over the age of 65.

The risk of gallbladder cancer correlates with the increasing size of gallstones, and the epidemiology of cholelithiasis parallels that of gallbladder carcinoma. American Indians, Northeastern Europeans, Israelis, and Mexican Americans have a high incidence of gallbladder cancer. Black Americans and Africans have the lowest incidence. Although Americans in general have a 8 to 17 per cent incidence of cholelithiasis, gallstones are uncommon among black Americans. Patients may have cholelithiasis for 10 to 25 years without developing gallbladder cancer, and in autopsy studies only 1 to 2 per cent of patients with cholelithiasis harbour gallbladder carcinoma. Chronic cholecystitis is also associated with gallbladder carcinoma. End-stage chronic cholecystitis leads to a calcified or porcelain gallbladder. The incidence of gallbladder cancer in calcified (porcelain) gallbladders has been reported to range from 12 to 60 per cent, but the issue has not been subjected to epidemiological scrutiny.

Chemical carcinogens such as methylcholanthrene, dimethylnitrosamine, and &agr;-aminoazotoluene induce gallbladder carcinoma in laboratory animals. The California Tumor Registry reported an increased incidence of gallbladder cancer in people who worked in rubber, automobile, wood-finishing, and metal-fabricating industries. However, despite 28 per cent of patients with gallbladder cancer in Akron, Ohio having worked in the rubber industry, the incidence of gallbladder carcinoma in the city was no higher than that reported across the United States.

An anomalous pancreaticobiliary ductal junction is associated with a 15 to 25 per cent incidence of gallbladder cancer. Such a junction allows bile and pancreatic juice to mix activating phospholipase A&sub2;. This leads to increasing concentrations of lysophosphatidylcholine, which have cytotoxic effects, and cause mucosal hyperplasia and metaplasia, conditions that are almost obligatory substrates for carcinogenesis (Fig. 1) 1275. Endoscopic retrograde cholangiopancreatography revealed an anomalous pancreaticobiliary ductal union in 16.7 per cent of 95 patients with gallbladder cancer. An anomalous union was noted in only 2.8 per cent of 681 patients with hepatobiliary or pancreatic diseases excluding gallbladder carcinoma.

Adenomyomatosis, gallbladder adenomas, and epithelial dysplasia may be associated with gallbladder carcinoma. There are reports of gallbladder carcinoma arising in areas of adenomyomatosis. Epithelial dysplasia was found in 83 per cent of gallbladders resected for cholelithiasis, atypical hyperplasia was present in 13.5 per cent of the specimens, and carcinoma in situ in 3.5 per cent. One case of dysplasia occurred within an area of metaplasia in 277 cholecystectomy specimens, while dysplasia of metaplastic epithelium surrounded the neoplasm in 67 per cent of 15 carcinomatous specimens, suggesting that carcinoma may arise from the progression of metaplasia or hyperplasia to dysplasia and carcinoma. Since ultrasound examination has become widespread, the detection rate of gallbladder polyps has increased. In 1605 cholecystectomy specimens, 11 harboured benign adenomas, seven harboured adenomas with malignant change, and 79 harboured invasive carcinomas. A histological transition from benign adenoma to malignant carcinoma was recognized. All benign lesions were less than 12 mm in diameter.

Gallbladder carcinoma manifests itself with thickening of the gallbladder wall, most often with the cancer originating in the gallbladder fundus. As the tumour progresses, the gallbladder may fill with tumour or may contain a mucinous exudate, with or without gallstones. Occasionally, the proteinaceous material within the lumen becomes infected and leads to cholangitis, either concomitantly or as a consequence.

Virtually all gallbladder cancer (80–95 per cent) is adenocarcinoma, the histological forms of which are papillary, tubular, mucinous, and signet-ring cell types. Undifferentiated or anaplastic carcinoma represents 2 to 7 per cent of cases, squamous cell cancer 2 to 5 per cent of cases, and adenoacanthoma or mixed adenosquamous tumour 1 to 3 per cent of cases. Carcinoid tumours, malignant melanoma, clear cell carcinoma, and spindle cell malignancies rarely occur.

Gallbladder cancer tends to spread locally, rather than by metastasis. The problem is that local spread can occur by lymphatic, vascular, intraneural, or intraductal invasion. Multiple channels of dissemination are responsible for the limited ability to restrain or cure the neoplasm. Direct invasion of the hepatic bed in the gallbladder fossa is seen in 45 to 90 per cent of patients with disseminated disease. The lymphatic drainage of the gallbladder begins in the intramural plexus, moves to the cystic nodes, into the hiatal nodes, to the superior and posterior pancreaticoduodenal nodes and, finally, to the periaortic chain. Lymphatic extension occurs in 20 to 70 per cent of cases. The venous drainage of the gallbladder is shown in Fig. 2 1276. The number of cholecystic veins on the hepatic side of the gallbladder ranges from two to 20; these drain directly into segment IV of the liver. The venous drainage of the peritoneal side of the gallbladder consists of one or two veins that also drain into segment IV of the liver and rarely empty into the portal vein. Vascular extension is seen in 10 to 20 per cent of cases. Tumour spreads through the neural sheath in 24 per cent of patients and intraductally through the biliary system in 19 per cent.

Because the symptoms of gallbladder carcinoma are generally non-specific, the tumour is discovered either incidentally or at an advanced stage. Cancer is found in approximately 1 per cent of gallbladders removed for benign disease. Advanced disease commonly presents itself with multiple symptoms including abdominal pain, nausea and vomiting, weight loss, jaundice, anorexia, abdominal distension, and pruritus. Patients may have a palpable right upper quadrant mass. Eighty per cent of patients have symptoms for less than 6 months prior to their presentation. In only 10 to 25 per cent of patients is the correct diagnosis made before surgery. Laboratory tests, although abnormal, are non-specific. An arteriographic CT portogram, in which the superior mesenteric artery is injected with contrast material, is the best way to assess a gallbladder carcinoma for resectability. Neoplasms tend to be hypervascular and arteriographic CT portography delineates the extent of disease. Ultrasound findings of marked gallbladder wall thickening, of a complex mass filling the gallbladder, or of a polypoid or fungating tumour filling the gallbladder are indicative of carcinoma. Abdominal CT diagnoses gallbladder cancer with a 66 per cent accuracy.

At least five staging systems for gallbladder carcinoma exist. Nevin devised a system from a review of 66 cases and a literature review of 399 cases that divided disease into five stages (Table 1) 370. The Mayo Clinic proposed a modification of the Nevin system by placing contiguous extension of tumour into the liver into stage III rather than into stage V. The American Joint Commission on Cancer and the Union Internationale Centre de Cancer (UICC) established a staging system using the TNM classification with four stages (Table 2) 371. Japanese surgeons stage gallbladder carcinoma according to the General Rules for Staging Carcinoma of the Biliary Tract into four stages. Another staging system was proposed in Japan which delineates patients into three stages. The lack of a definitive staging system for gallbladder carcinoma has made comparison of series of patients and analysis of results difficult to interpret.

Only surgery can cure gallbladder cancer: a universally accepted surgical treatment of gallbladder cancer does not exist. Only 10 to 30 per cent of patients have resectable disease on presentation.

Early experience failed to show a survival benefit following extensive resection: radical resection therefore fell out of favour. Modern delineation of the modes of spread of gallbladder cancer, however, has led to a resurgence of radical resection in an effort to remove microscopic tumour completely. The extent of radical surgery ranges from cholecystectomy with an accompanying hepatic wedge resection to an extensive resection including cholecystectomy, extended right hepatectomy, and pancreaticoduodenectomy with local and para-aortic lymphadenectomy. Anecdotal reports of long-term survival in patients with extensive disease following large extirpative procedures are common, but the morbidity rates associated with extensive resection reach 54 per cent, and mortality rates are around 5 per cent.

Direct comparisons between the results of radical and non-radical surgery do not show statistically significant differences in patient survival despite the attendant increases in morbidity and mortality. Both the Mayo Clinic and the Massachusetts General Hospital compared cholecystectomy with cholecystectomy and hepatic wedge resection and noted no statistically significant survival advantage. There is little evidence to support radical surgery for advanced disease.

Surgical treatment for incidentally discovered gallbladder carcinoma also remains controversial. In a Swedish study of 32 patients who underwent a cholecystectomy and were found to have microscopic gallbladder cancer, the 5-year survival rate was 64 per cent and the 10-year survival rate was 44 per cent when the tumour extended only to the gallbladder serosa. When tumour extended through the serosa, the 1-year survival rate was 30 per cent. Numerous reports cite a 100 per cent 5-year survival rate when tumour is limited to the gallbladder mucosa.

In a Japanese study of patients with inapparent carcinoma, 35 of 45 patients with tumour extending to the gallbladder serosa, but not through it, underwent cholecystectomy alone, with a 40 per cent 5-year survival. However, 10 patients who underwent cholecystectomy followed at a second operation by hepatic wedge resection, common bile duct resection and en-bloc dissection of regional lymph nodes had a 90 per cent 5-year survival rate. An increased survival rate was not seen in patients whose tumour extended through the gallbladder serosa. All patients with disease limited to the mucosa survived 5 years following cholecystectomy.

The effectiveness of adjuvant therapy in gallbladder cancer is unpredictable. The Eastern Cooperative Oncologic Group reported a randomized trial of 5-fluorouracil alone, 5-fluorouracil with streptozotocin, and 5-fluorouracil with methyl-CCNU. There was no difference in survival rates between regimens or compared with historical controls who received no chemotherapy. A non-significantly increased survival rate was found in a comparison of hepatic arterial infusion of mitomycin-C and 5-fluorouracil and controls.

Radiation therapy provides symptomatic relief. Eighty per cent of patients with end-stage gallbladder cancer reported palliation of pruritus and pain when treated with external beam radiation therapy with doses ranging from 3200 to 5000 cGy. Twenty patients who underwent postoperative radiation therapy (mean, 4200 cGy) showed no increase in survival rates over historical controls.

Intraoperative administration of radiation increases its specificity and intensity. Ten patients received such therapy for either gross residual disease or completely unresected disease with a median survival of 1 year. Seventeen patients who underwent radical resection combined with intraoperative radiation therapy were compared with nine patients who underwent radical resection alone. There was a small but statistically significant increase in (p < 0.05) 3-year survival among patients who received intraoperative radiation therapy. Intraoperative radiation therapy itself does not appear significantly to improve survival. Implantation of iridium-192 wire into the common bile duct is sometimes effective as palliative treatment, but rarely cures malignant biliary obstruction. Although cholangitis is a frequent complication of intraductal brachytherapy, its incidence can be decreased by endoscopically placing a 10 Fr biliary stent into the biliary duct 2 weeks before the iridium-192. As with other adjuvant therapeutic modalities the number of patients reported is small, patients so treated have usually had bile duct carcinoma, and the results are inconclusive.

Gallbladder cancer has a poor prognosis. The overall 5-year survival rate is approximately 5 per cent. Despite increasingly aggressive surgical resection, no improvement in survival has occurred in the last 30 years. Adjuvant therapy is ineffective. Simple cholecystectomy with postoperative radiation therapy is the treatment of choice for limited disease. Cholecystectomy and an accompanying biliary bypass procedure, when possible, are appropriate for extensive disease.

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