Biliary Tract Surgery

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Carcinoma of the Gallbladder

R. Scott Jones, MD*

Primary gallbladder cancer, the most common malignant lesion of the biliary tract, ranks fifth in frequency among digestive tract cancers. 19 In the United States, 2.5 per 100,000 residents develop carcinoma of the gallbladder,? and in 1936, 6500 Americans died from this cancer. Approximately 0.55% of all autopsies disclose a carcinoma of the gallbladder. Surgeons should remember that they will encounter gallbladder cancer during 1% to 2% of all biliary tract operations.v' Regarding racial origin, gallbladder cancer occurs six times more frequently in southwest American Indians than in the non-Indian population.P Also, Japanese-Americans have higher rates of gallbladder cancer than other populations.:" Gallbladder cancer occurs more commonly in women, with a female-to-male ratio of 3:1. 42 The disease increases considerably with age. The mean age of patients with carcinoma of the gallbladder is 65.2 years, with the highest incidence of the disease in the seventh and eighth decades of life42 (Table 1).

PATHOGENESIS The cause of gallbladder cancer remains unknown. However, several factors associated with the disease deserve comment. Gallstones frequently accompany gallbladder cancer: three fourths of patients with a diagnosis of cancer of the gallbladder have cholelithiasis, suggesting that gallstones cause the cancer. However, the fact that one fourth of patients do not have gallstones argues against such a causal role." 17, 20, 41 Furthermore, patients can have asymptomatic gallstones for as long as 10 to 25 years without the development of gallbladder cancer." Autopsy studies reveal an incidence of cancer in the gallbladder of only 1% to 3% in patients with cholelithiasis. 42 In older subjects with gallstones, the estimated 20-year cumulative risk for gallbladder cancer range from 0.13% in black males to 1.5% in Indian females;" Therefore, although it is clear that there may be an increased *Stephen H. Watts Professor of Surgery and Chairman, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia

Surgical Clinics of North America-Vol. 70, No.6, December 1990

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incidence of gallstones in patients with cancer of the gallbladder, no definite causal relation between gallstones and cancer has been established. Patients with calcified gallbladders also have a high incidence of associated gallbladder cancer. 43 Animal studies suggest that carcinogens can cause gallbladder cancer. Methylcholanthrene pellets implanted in the wall of the gallbladder of dogs or cats produce carcinoma. 14, 15 Feeding other chemicals such as o-aminoazotoluene or nitrosamines also causes gallbladder cancer in experimental animals. 10, 14, 15, 24 A high incidence of gallbladder and biliary cancer in individuals working in the rubber industry suggests a link between these cancers and occupational factors, presumably the chemicals employed in this industry. 28 The role of benign neoplasms of the gallbladder in the development of gallbladder cancer remains unclear. Although carcinoma in situ occurs in benign gallbladder polyps, an important role for benign polyps in the development of gallbladder cancer remains uncertairr." Yamagiwa and Tomiyama studied 1000 gallbladders with careful histologic preparation and found intestinal metaplasia in 4% of the gallbladders without stones and 30.6% of the gallbladders containing stones. In addition, metaplasia occurred at rates of 69.8% in cases of dysplasia and 61.1% in cases of carcinoma of the gallbladder. Dysplasia and adenoma intermingled in the tumor tissue at the rate of 22.2% and 8.3% in the 36 cases of carcinoma of the gallbladder. 53 In another study of 2027 gallbladders, one of those authors found isolated dysplasia in 46 cases. He went on to suggest that the sequence of intestinal metaplasia to dysplasia to carcinoma may be important in the genesis of gallbladder cancer, especially in patients with gallstones. 52 Several authors have recently raised the question of whether anomalous pancreaticobiliary ductal union is associated with or plays a role in the development of gallbladder cancer. Kimura and others" studied 96 patients with gallbladder cancer in whom direct cholangiography clearly opacified the pancreaticobiliary ductal union and the common channel. They also studied 65 patients with an anomalous union of these two duct systems at a distance greater than 15 mm from the papilla of Vater. This anomalous ductal union occurred in 16.7% of the patients with gallbladder carcinoma in comparison with 2.8% of 641 consecutive patients with various hepatobiliary and pancreatic diseases studied by endoscopic retrograde cholangiopancreatography who did not have gallbladder carcinoma. Those investigators also found that gallbladder carcinoma occurred in 25% of the 65 Table 1. Carcinoma of the Gallbladder Uncommon malignancy: about 4000-6000 new cases per year Fifth most common gastrointestinal cancer Occurs most frequently in women (75%) Median age: seventh decade Common association with gallstones Usually first diagnosed by laparotomy Prognosis poor: 3% to 5% long-term survival rate in most series From Wanebo HJ: Carcinoma of the gallbladder. In Wanebo HJ (ed): Hepatic and Biliary Cancer. New York, Marcel Dekker, 1987, p 432; with permission.

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cases of anomalous ductal union in comparison with a 1.9% incidence of this cancer among 635 consecutive patients similarly studied and found to have a normal ductal union." Several other authors have also suggested a relation between anomalous pancreaticobiliary ductal union and carcinoma of the gallbladder. 31, 32, 34, 47, 55

HISTOLOGIC FINDINGS AND SPREAD Carcinoma of the gallbladder usually produces diffuse thickening of the wall of the organ, usually in the fundus, and the process may infiltrate surrounding structures. Occasionally, polypoid or papillary tumors project into the lumen. The histologic types of gallbladder cancer, in decreasing order of frequency, are adenocarcinoma, undifferentiated carcinoma, squamous carcinoma, adenoacanthoma, and carcinoma in situ. Other malignant lesions occurring rarely in the gallbladder are carcinoid tumors and malignant melanomas. 4, 40 Fahim and associates, who worked at the Mayo Clinic, clearly described the mode of spread of carcinoma of the gallbladder.": 12 The means of spread were found to be lymphatic, vascular, neural, intraperitoneal, intraductal, and through direct extension. The lymph from the gallbladder drains from intramural plexuses to lymph nodes along the biliary ductal system into the superior and posterior pancreaticoduodenal nodes and then to the periaortic chain. Thus, the lymph draining from the gallbladder principally passes through a region along the right side of the common duct. Early nodal metastases from the gallbladder appear in the cystic duct node and the pericholeductal nodes, and later, metastases develop in the periaortic nodes. The incidence of lymph node metastasis from cancer of the gallbladder at the time of evaluation ranges from 25% to 75%. The venous blood from the gallbladder drains into segment IV of the liver by short, direct communicating veins or by veins accompanying the extrahepatic ducts into the liver. This drainage explains the initial localized metastasis of gallbladder cancers into the liver adjacent to the gallbladder rather than to distant sites in the liver. Fahim and associates demonstrated microscopic vein invasion in 13.9% of their cases. H The tumors may spread intraperitoneally by local invasion to the liver, stomach, duodenum, colon, or abdominal wall with occasional fistula formation; however, disseminated intraperitoneal metastases from the carcinoma of the gallbladder are uncommon. Gallbladder cancers can spread by the intraductal route, and their behavior is characteristic of papillary malignancies.

DIAGNOSIS Carcinoma of the gallbladder produces symptoms that include, in decreasing order of frequency, pain, nausea, vomiting, weight loss, and jaundice (Table 2). The relatively nonspecific symptoms of gallbladder cancer have been organized into five clinical syndromes in an excellent review by Piehler and Crichlow. 42

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Table 2. Gallbladder Cancer Symptoms in the University of Virginia Series, 1981 SYMPTOM

PER CENT OF PATIENTS*

Pain Nausea and vomiting Weight loss Jaundice Anorexia Abdominal distention Pruritus Melena

79 53 42

DURATION

Carcinoma of the gallbladder.

Gallbladder cancer remains difficult to diagnose preoperatively. However, recent work suggests that ultrasound may be effective. Gallbladder cancer re...
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