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Gallbladder Tumors

  • Author: Thomas J VanderMeer, MD; Chief Editor: John Geibel, MD, DSc, MSc, MA  more...
 
Updated: Jun 19, 2015
 

Background

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. 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 size of a gallbladder polyp is generally the strongest predictor of malignant transformation.[1]

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.

In 1924, Blalock suggested avoiding surgery on patients with gallbladder cancer if the diagnosis could be made preoperatively.[2] 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.

The surgical approach to gallbladder cancer includes prevention, early detection, appropriate staging, and curative resection.

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.

Malignant lesions

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.[3]

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.[4, 5] 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.

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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.[6]

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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.[7]

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.

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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/m2 increase in the body-mass index, is strongly associated with an increased risk of gallbladder cancer.[8]

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Epidemiology

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 10,910 new cases of gallbladder cancer would be diagnosed in 2015 and that there would be 3700 deaths from the disease.[3] The incidence of gallbladder cancer is 1.2 per 100,000 persons in the United States.[9]  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.[7]

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Prognosis

The overall survival rate for adenocarcinoma of the gall bladder depends on the stage at presentation. For T1 lesions, many studies report 5-year survival rates of 100%, especially when hepatectomy is used routinely for T1b or deeper lesions.

The 5-year survival rates following extended cholecystectomy for T2 lesions ranges in the literature from 38% to 77%. Tumor location may affect survival for T2 lesions. In one study, of 252 patients who underwent curative resection for T2 disease, those with tumors on the hepatic side had higher rates of vascular invasion, neural invasion, and nodal metastasis and lower 3- and 5-year survival rates than patients with tumors on the peritoneal side.[10]

Extended resection is necessary for stage III and IV tumors and results in 5-year survival of about 25%.

Patients with unresectable disease have a median survival of 2-4 months and a 1-year survival rate of less than 5%.[7, 11]

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Contributor Information and Disclosures
Author

Thomas J VanderMeer, MD Assistant Professor of Surgery, SUNY Upsate Medical University; Program Director, General Surgery Residency; Chief, Section of General Surgery, Guthrie Health; Sayre, PA

Thomas J VanderMeer, MD is a member of the following medical societies: American College of Surgeons, Association for Surgical Education, Society for Surgery of the Alimentary Tract, Americas Hepato-Pancreato-Biliary Association, American College of Surgeons Oncology Group, Association of Program Directors in Surgery

Disclosure: Nothing to disclose.

Coauthor(s)

Michel M Murr, MD Professor, Department of Surgery, Director of Bariatric Surgery, University of South Florida

Michel M Murr, MD is a member of the following medical societies: American College of Surgeons, Americas Hepato-Pancreato-Biliary Association, American Society for Metabolic and Bariatric Surgery, Association for Academic Surgery, International College of Surgeons US Section, Society for Surgery of the Alimentary Tract, Southeastern Surgical Congress

Disclosure: Received consulting fee from Covidien for consulting.

Michael Kent McLeod, MD, MBA, FACE, FACS Associate Chair, Professor of Surgery and Program Director, Integrated General Surgery Program, Department of Surgery, Michigan State University College of Human Medicine

Michael Kent McLeod, MD, MBA, FACE, FACS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Surgeons, American Medical Association, Association for Academic Surgery, Central Surgical Association, International Association of Endocrine Surgeons, Michigan State Medical Society, Midwest Surgical Association, National Medical Association, Society of American Gastrointestinal and Endoscopic Surgeons, Western Surgical Association, American Association of Endocrine Surgeons

Disclosure: Nothing to disclose.

Tara Mancl, MD Staff Physician, Department of Surgery, Michigan State University, Kalamazoo Center for Medical Studies

Tara Mancl, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Family Physicians, American College of Surgeons, American Medical Student Association/Foundation

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

John Geibel, MD, DSc, MSc, MA Vice Chair and Professor, Department of Surgery, Section of Gastrointestinal Medicine, and Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director, Surgical Research, Department of Surgery, Yale-New Haven Hospital; American Gastroenterological Association Fellow

John Geibel, MD, DSc, MSc, MA is a member of the following medical societies: American Gastroenterological Association, American Physiological Society, American Society of Nephrology, Association for Academic Surgery, International Society of Nephrology, New York Academy of Sciences, Society for Surgery of the Alimentary Tract

Disclosure: Received royalty from AMGEN for consulting; Received ownership interest from Ardelyx for consulting.

Acknowledgements

Michael A Grosso, MD Consulting Staff, Department of Cardiothoracic Surgery, St Francis Hospital

Michael A Grosso, MD is a member of the following medical societies: American College of Surgeons, Society of Thoracic Surgeons, and Society of University Surgeons

Disclosure: Nothing to disclose.

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A schematic drawing of the extent of lymphadenectomy for gallbladder cancer, especially when the extrahepatic biliary tree is resected.
Gallbladder tumors. A schematic drawing of the extent of resection of liver segments IV-b and V for gallbladder cancer.
Sagittal ultrasonogram in a 71-year-old woman. This image demonstrates heterogeneous thickening of the gallbladder wall (arrows). The diagnosis was primary papillary adenocarcinoma of the gallbladder.
A transaxial enhanced computed tomography (CT) scan of a 60-year-old man with right upper quadrant pain shows a partially calcified gallbladder (arrow). At laparotomy and histology, an infiltrating adenocarcinoma of the gallbladder was confirmed.
Computed tomography (CT) scan in a 65-year-old man. This image depicts squamous cell carcinoma of the gallbladder and invasion of the liver.
Table 1. AJCC TNM Classification of Gallbladder Tumors
Tumor (T), Node (N), Metastasis (M) Description
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor invades lamina propria or muscle layer



See the list below:



  • T1a - Tumor invades lamina propria
  • T1b - Tumor invades the muscularis
T2 Tumor invades the perimuscular connective tissue; no extension beyond the serosa or into the liver
T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or 1 other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts
T4 Tumor invades the main portal vein or hepatic artery or invades multiple extrahepatic organs or structures
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Portal lymph node metastasis
N2 Distant lymph node metastasis such as periaortic, pericaval, superior mesenteric artery, or celiac artery
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Table 2. AJCC Staging of Gallbladder Tumors According to TNM Classification
AJCC Stage TNM
0 Tis, N0, M0
I T1 (a or b), N0, M0
II T2, N0, M0
IIIA T3, N0, M0
IIIB T1-3, N1, M0
IVA T4, N0-1, M0
IVB Any T, N2, M0



Any T, any N, M1



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