eMedicine Specialties > General Surgery > Abdomen

Gallbladder Tumors

Author: Thomas J VanderMeer, MD, Assistant Professor of Surgery, SUNY Upstate Medical University; Program Director, General Surgery Residency; Chief, Section of General Surgery, Guthrie Health; Sayre, PA
Coauthor(s): Michael K McLeod, MD, FACE, FACS, Professor of Surgery and Program Director, Integrated General Surgery Program, Department of Surgery, Michigan State University College of Human Medicine; Tara Mancl, MD, Staff Physician, Department of Surgery, Michigan State University, Kalamazoo Center for Medical Studies; Michel M Murr, MD, Professor, Department of Surgery, Director of Bariatric Surgery, University of South Florida
Contributor Information and Disclosures

Updated: Apr 15, 2009

Introduction

Gallbladder tumors are recognized with increasing frequency due to improvements in imaging techniques and increased utilization of these studies. Approximately 5% of patients evaluated with ultrasonography for abdominal pain will have a gallbladder polyp. Cancer of the gallbladder is uncommon, although it is the fifth most common gastrointestinal malignancy. The size of a gallbladder polyp is generally the strongest predictor of malignant transformation. (See image below.)

Benign lesions of the gallbladder are relatively common, but only adenomatous polyps are considered to have malignant potential. Although ultrasonography can be useful in evaluating these lesions, considerable difficulty may be encountered in establishing the diagnosis preoperatively.

Cholesterol polyps

Cholesterol polyps account for approximately 50% of all polypoid lesions of the gallbladder.

These lesions are thought to originate from a defect in cholesterol metabolism. They appear as yellow spots on the mucosal surface of the gallbladder and are identified histologically as epithelial-covered macrophages laden with triglycerides and esterified sterols in the lamina propria of the mucosal layer of the gallbladder.

As a rule, cholesterol polyps exist as multiple lesions and are usually less than 10 mm. Cholesterol polyps are generally asymptomatic.

Inflammatory polyps

These lesions result from chronic inflammation. They extend into the gallbladder lumen by a narrow vascularized stalk.

Adenomyomatosis

Adenomyomatosis is characterized by extensions of Rokitansky-Aschoff sinuses through the muscular wall of the gallbladder. Ultrasonography reveals a thickened gallbladder wall with intramural diverticula. Although adenomyomatosis is generally considered a benign condition, serial evaluation with ultrasonography is indicated to rule out enlarging adenomatous polyps and gallbladder cancer. Some authors have reported gallbladder cancer occurring in localized adenomyomatosis and have suggested a more aggressive approach to the benign lesions.

Adenomatous polyps

Adenomatous polyps are benign epithelial neoplasms with malignant potential. Papillary adenomas grow as pedunculated, complex, branching tumors projecting into the gallbladder lumen. Tubular adenomas arise as a flat, sessile neoplasm. Consequently, it can be difficult to distinguish some adenomas from other gallbladder polyps by ultrasonography. Like many gastrointestinal tumors, an adenoma-carcinoma sequence is generally thought to occur in these lesions.

Other lesions

Other rare, benign lesions found in the gallbladder include fibromas, leiomyomas, lipomas, hemangiomata, granular cell tumors, and heterotropic tissue, including gastric, pancreatic, and intestinal epithelium.

The incidence of gallbladder cancer is 1.2 cases 100,000 persons in the United States; the frequency is much higher in Mexican Americans and Native Americans, although the greatest incidence is found in the indigenous peoples of the Andes Mountains, in northeastern Europeans, and in Israelis. The female-to-male ratio for gallbladder cancer is about 3:1; incidence of the disease peaks in the seventh decade of life.¹

The most common risk factor for gallbladder cancer is gallstones, which are present in 75%-90% of gallbladder cancer cases. The size of the gallstones plays a role in the risk of developing of gallbladder cancer. Gallbladders containing gallstones that are greater than 3 cm in diameter have a 10-fold greater risk for developing malignancy than do those containing gallstones that are 1 cm in diameter. Causality is difficult to establish, but other chronic inflammatory conditions, such as cholecystoenteric fistula, primary sclerosing cholangitis, pancreaticobiliary maljunction, and chronic infection with Salmonella typhi, have also been associated with an increased risk of gallbladder cancer.

Modern series report about a 10% incidence of gallbladder cancer in porcelain gallbladders (in which the gallbladder wall is calcified), a much lower rate than that reported in older series. Stippled calcification of the mucosa is thought to carry a higher risk of gallbladder cancer than does generalized calcification of the gallbladder wall.^2,3 Based on these associations, chronic inflammation is postulated to be involved in the pathogenesis of gallbladder cancer.

Gallbladder cancer is often discovered incidentally during a workup for gallstone disease, and about 50% of gallbladder cancer cases are diagnosed incidentally in cholecystectomy specimens. Unfortunately, about 35% of patients have distant metastases at the time of diagnosis.

Histologically, adenocarcinoma is found in 90% of gallbladder cancer cases, and squamous cell carcinoma is found in 2% of cases. Rare types of gallbladder cancer include sarcoma, adenosquamous carcinoma, oat cell carcinoma, carcinoid, lymphoma, melanoma, and metastatic tumors. A number of histologic subtypes of adenocarcinoma have been described, but papillary adenocarcinoma represents about 5% of gallbladder cancers; it tends to be well-differentiated and carries a more favorable prognosis. (See images below.)

History of the Procedure

In 1924, Blalock suggested avoiding surgery on patients with gallbladder cancer if the diagnosis could be made preoperatively.⁴  Therapeutic nihilism continued to define the approach to gallbladder cancer through most of the 20th century. Although most patients with gallbladder cancer continue to present with advanced disease, advances in imaging and hepatobiliary surgical techniques have made curative surgery possible in a greater number of cases.

Problem

It is possible to cure gallbladder cancer when tumors are treated surgically at an early stage. Since gallbladder polyps are common, it is important to identify those that carry a high risk of malignancy. The surgical approach to gallbladder cancer includes prevention, early detection, appropriate staging, and curative resection.

Frequency

Approximately 5% of patients evaluated with ultrasonography for abdominal pain will have a gallbladder polyp. Adenomatous polyps are found in about 1% of cholecystectomy specimens. The American Cancer Society estimated that 9,520 new cases of gallbladder cancer would be diagnosed in 2008 and that there would be 3,340 deaths from the disease.¹ The incidence of gallbladder cancer is 1.2 per 100,000 persons in the United States.⁵  Mexican Americans and Native Americans have a greater incidence of gallbladder cancer than do other North American populations, while the highest incidences worldwide are found in the native peoples of the Andes Mountains, in northeastern Europeans, and in Israelis. The female-to-male ratio for gallbladder cancer is about 3:1; incidence of the disease peaks in the seventh decade of life.⁶

Etiology

Gallstones are present in 75-90% of gallbladder cancer cases, but an etiologic influence remains unproven. Risk factors for developing gallbladder cancer include the inflammatory conditions listed above, advanced age, and the presence of a gallstone larger than 3 cm. Anomalous pancreatobiliary junction also may be a risk factor for the development of gallbladder cancer. Some authors have implicated bile acid composition, methyldopa, oral contraceptives, and occupational exposure to rubber, but these associations remain unproven. A 2008 study found evidence that excess body weight in women, specifically a 5 kg/m ² increase in the body-mass index, is strongly associated with an increased risk of gallbladder cancer.⁷

Pathophysiology

Chronic inflammation from a variety of stimuli has been implicated in the pathogenesis of gallbladder cancer. Numerous studies have investigated genetic abnormalities in gallbladder cancer and have shown that approximately 39-59% of gallbladder cancers are associated with the K-ras mutation, while more than 90% of them are associated with a p53 mutation. Other studies have identified higher levels of microsatellite instability and loss of heterozygosity when gallbladder cancers develop in a background of chronic cholecystitis. A number of other genetic abnormalities have been associated with gallbladder cancer including overexpression of the c-erb-2 gene, upregulation of cyclin D1, p16, p27, and MSH2.⁶

An adenoma-carcinoma sequence is thought to be involved in many cases of gallbladder cancer. Gallbladder cancer spreads early via lymphatic, hematogenous, and transcoelomic dissemination. Local invasion into the liver and surrounding organs is common.

Presentation

As with most gallbladder lesions, early stage adenocarcinoma tends to present with symptoms similar to cholelithiasis or biliary dyskinesia. Advanced gallbladder cancer presents with more significant symptoms, such as weight loss, jaundice, anorexia, ascites, and right upper quadrant mass.

Given this presentation, less than 50% of gallbladder cancers are diagnosed preoperatively. Many are diagnosed incidentally in gallbladders removed for biliary colic or cholecystitis. Unfortunately, most gallbladder cancers are diagnosed in the later stages, and the overall 5 year survival rate is less than 5%.

Indications

Cholecystectomy is recommended for suspicious gallbladder polyps in order to facilitate early detection and treatment. Risk factors for malignancy include a polyp greater than 1 cm in size, primary sclerosing cholangitis, the presence of a single polyp, and a patient age of greater than 50 years. Ultrasonographic findings of vascularity and invasion of the gallbladder wall are suspicious findings. One study demonstrated that 7.4% of gallbladder polyps that were less than or equal to 1 cm were neoplastic.⁸ The report's authors recommended cholecystectomy for lesions that are greater than or equal to 6 mm.

Gallbladder cancer is diagnosed incidentally following cholecystectomy or based on preoperative imaging. The surgical indications are based on stage and margin status. Incidentally discovered T1a gallbladder cancers (which are limited to the mucosa) can be treated with cholecystectomy alone. T1b tumors (which invade the muscle layer) are treated with resection of liver segments IVb and V and portal lymph node dissection. Bile duct resection is sometimes required to achieve a negative margin, especially if the cystic duct margin was positive on the cholecystectomy specimen. T2 and T3 lesions are also treated with liver resection and portal lymph node dissection, but extended right hepatectomy may be necessary to achieve negative margins.⁶ (See images below.)

Relevant Anatomy

The gallbladder is a saccular structure located at the inferior surface of the liver, at the division of the right and left lobes, just below segments IV and V. The gallbladder is composed of 4 different areas: the fundus, body, infundibulum, and neck. The gallbladder is approximately 7-10 cm long and about 2.5-3.5 cm wide. It normally contains approximately 30-50 mL of fluid, but it can distend and hold up to 300 mL of fluid. Gallbladder cancer generally spreads via the lymphatic channels and venous drainage, and peritoneal metastasis is common. Since the gallbladder is immediately adjacent to the liver, bile duct, portal vein, hepatic artery, duodenum, and transverse colon, involvement of these structures is common.

The cystic plate is the reflection of the visceral peritoneum between the liver and the gallbladder. The dissection between the gallbladder and the liver during cholecystectomy divides the plane between the cystic plate and the muscle layer of the gallbladder. This is the anatomic basis for the improved survival in patients undergoing liver resection for T1b gallbladder cancer.
 
The lymphatic drainage of the gallbladder proceeds from the cystic node to the pericholedochal nodes and then to the regional nodal basins, including the superior mesenteric, retropancreatic, retroportal, and celiac. Interestingly, direct drainage from the gallbladder to the aortocaval nodes has been demonstrated. For this reason, exposure of this region is a necessary step in the operative staging of gallbladder cancer.⁹

Contraindications

Contraindications to surgery with curative intent include the presence of distant metastatic disease (including biopsy-proven metastatic aortocaval lymphadenopathy), T4 lesion (local invasion of the hepatic artery, main portal vein, and multiple adjacent structures), and inability to obtain a negative margin. Most North American surgeons consider the presence of celiac and retroperitoneal lymph node metastases a contraindication to resection because of the poor oncologic outcome of these patients with currently available treatment. For the same reason, some controversy exists about the benefit of resecting patients with T3 lesions. Some patients may be technically resectable but unable to tolerate the necessary procedure.

• Search for CME/CE on This Topic »

• Gallbladder, Carcinoma (Radiology)