eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Gallbladder Cancer

Author: Mary Denshaw-Burke, MD, FACP, Assistant Clinical Professor, Department of Medicine, Thomas Jefferson University School of Medicine; Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Hospital; Consulting Staff, Lankenau Hospital, Delaware County Memorial Hospital, Mercy Fitzgerald Hospital, Bryn Mawr Hospital, Taylor Hospital
Coauthor(s): Jessica B Katz, MD, PhD, FACP, Hematology/Oncology Fellowship, Lankenau Hospital; Churchman Fellow, Lankenau Institute of Medical Research; Andrew Scott Kennedy, MD, Co-Medical Director, Wake Radiology Oncology; David Van Echo, MD, Head, New Drug Development Program (Oncology), Professor, Departments of Medicine and Pharmacy, University of Maryland School of Medicine; Director of HarborView Cancer Center
Contributor Information and Disclosures

Updated: Jun 12, 2008

Introduction

Background

Cancers of the biliary tract include cholangiocarcinoma (cancers arising from the bile duct epithelium), ampulla of Vater cancer, and gallbladder cancer. All subtypes of biliary tract cancers are rare and have an overall poor prognosis. They are also difficult to diagnose. These diseases are often discussed together and are mingled in therapeutic trials. However, this leads to significant confusion. Gallbladder cancer is the fifth most common GI cancer in the United States and the most common hepatobiliary cancer. According to 1992-2000 data from the Surveillance, Epidemiology, and End Results (SEER) program, gallbladder cancer accounts for 46% of the biliary tract cancers in the United States.1  About 20% arise from the extrahepatic biliary tract and 20% arise from the ampulla of Vater.2 Despite some similarities, gallbladder cancer is a distinct clinical entity and will be discussed exclusively in this article.

Pathophysiology

Gallbladder cancer arises in the setting of chronic inflammation. In the vast majority of patients (>75%), the source of this chronic inflammation is cholesterol gallstones. The presence of gallstones increases the risk of gallbladder cancer 4- to 5-fold.3 Other more unusual causes of chronic inflammation are also associated with gallbladder cancer. These causes include primary sclerosing cholangitis, ulcerative colitis,4 liver flukes, chronic Salmonella typhi and paratyphi infections,5 and Helicobacter infection.6

However, chronic gallbladder inflammation is likely only part of the cause of the malignant transformation seen in gallbladder cancer. Many other factors have been identified. Ingestion of certain medications (eg, oral contraceptives, INH, methyldopa) can increase the risk of gallbladder cancer. Likewise, certain chemical exposures (eg, pesticides, rubber, vinyl chloride) and occupational exposures associated with working in the textile, petroleum, paper mill, and shoemaking industries increase the risk of gallbladder cancer. In addition, exposures through water pollution (organopesticides, eg, dichlorodiphenyltrichloroethane and benzene hexachloride); heavy metals (eg, cadmium, chromium, lead); and radiation exposure (eg, radon in miners) are associated with gallbladder cancer.  Obesity7 may contribute to gallbladder cancer through its association with gallstones, its association with increased endogenous estrogens, or through the ability of fat cells to secrete a large number of inflammatory mediators.2 Related CME is available at Excess Body Weight Increases Risk for Many Cancers.

An increased incidence of gallbladder cancer also occurs in hereditary syndromes including Gardner syndrome, neurofibromatosis type I, and hereditary nonpolyposis colon cancer.2 The role of various oncogenic mutations in gallbladder cancer is an area of active research. For example, a small study of gallbladder cancer from Japan reported an excess risk associated with polymorphism of the cytochrome P450 1A1 gene (CYP1A1), which encodes a protein involved in catalyzing the synthesis of cholesterol and other lipids.8  Another study looked at polymorphisms within the apolipoprotein B gene.9

Abnormal anatomy such as congenital defects with anomalous pancreaticobiliary duct junctions and choledochal cysts increase the risk of gallbladder cancer.10,11  The tumor is usually located in the fundus of the gallbladder. Local spread through the gallbladder wall can lead to direct liver invasion, or, if in the opposite direction, leads to transperitoneal spread (20% of patients at presentation), with implants on the liver, on the bowel, and in the pelvis. Tumor may also directly invade other adjacent organs such as the stomach, duodenum, colon, pancreas, and extrahepatic bile duct. At diagnosis, the gallbladder is often replaced or destroyed by the cancer, and approximately 50% of patients have regional lymph node metastases.

See the Gallbladder and Biliary Disease Resource Center for more information about related conditions.

Frequency

United States

Approximately 9000 new cases of gallbladder cancer and other biliary cancers are predicted for 2008 according to the American Cancer Society. Gallbladder cancer incidence increases with age and is more common in women. According to the American Cancer Society 2008 statistic projections, the number of new cases of gallbladder and other biliary cancers in the United States in men is predicted to be 4500 and in women is predicted to be 5020.12

The number of deaths projected for 2008 in the United States according to the American Cancer Society is 1250 and 2090 for men and women, respectively. The total number of gallbladder and other biliary tract cancers for 2008 is 3340.12

In the United States, incidence varies substantially with racial and ethnic group and sex. Gallbladder cancer rates are the highest among American Indians/Alaska Natives and among white Hispanic peoples.  Within both groups, incidence of gallbladder cancer is significantly higher in women.2  The white Hispanic female incidence rate is 4.2 per 100,000 person-years. The American Indian/Alaskan Native female incidence rate is 4.1 per 100,000 person-years. The corresponding male rates are 1.4 and 3,3 per 100,000 person-years, respectively. The lowest incidence rate for gallbladder cancer is among non-Hispanic white males and is 0.7 per 100,000 person-years.

The incidence of gallbladder cancer rises with age. Seventy-five percent of patients with gallbladder cancer are older than 64 years.12 In non-Hispanic whites and blacks, the rate of gallbladder cancer rises more slowly than among Hispanic whites and American Indian/Alaskan Natives. The rates for gallbladder cancer are higher among women than men in all age groups.2

Overall, the incidence (cases per year) has dropped by more than 50% in the general population since 1973. In Native American women, the incidence has decreased by 70%.12

International

Considerable variation exists in the incidence of gallbladder cancer throughout the world. Areas with the highest incidence rates include India, Korea, Japan, CzechRepublic, Slovakia, Spain, Columbia, Chile, Peru, Bolivia, and Ecuador. The high incidence rates reported in Peru and Chile are thought to reflect the Hispanic populations with Indian heritage. Females from India have the highest international rate of gallbladder cancer at between 8.8 per 100,000 person-years and 21.2 per 100,000 person-years.2,5 The United Kingdom, Denmark, and Norway have the lowest international incidence rates. Gallbladder cancer is the most common cancer affecting women in Chile. 

Mortality/Morbidity

Survival is correlated with staging based on the American Joint Committee on Cancer (AJCC) tumor, node, metastases (TNM) staging system.13  Most patients have regional disease or distant metastases at presentation. Therefore, the prognosis in gallbladder disease is poor, with 5-year survival rates of 15-20%.2

Patients with stage IA disease (T1N0M0) should be cured with a simple cholecystectomy. In selected surgical series, patients with stage IB (T2N0M0) disease treated with extended cholecystectomy have a 5-year survival rate of 70-90%, and patients with stage IIB (T1-3N1M0) treated with extended cholecystectomy have a 5-year survival of 45-60%. Stage III (T4, any N, M0) gallbladder cancer is generally not surgically curable. The 1-year survival rate for advanced gallbladder cancer is less than 5%. The median survival is 2-4 months.

The SEER registry from 1995-2001 shows 5-year survival rates for localized gallbladder cancer of approximately 40%. The 5-year survival rate for regional disease is listed at approximately 15%, and the 5-year survival rate for distant metastatic disease is reported at less than 10%.1  However, survival data are variable from institution to institution for each stage. 

Unfortunately, only about 10-20% of patients present with tumor confined to the gallbladder wall. At diagnosis, 40-60% of patients have lesions that perforate the gallbladder wall and invade adjacent organs (T3) and 45% of patients have regional lymph node involvement (N1). Approximately 30% of patients present with metastatic disease.

Race

The highest rates of gallbladder cancer in the US are found in the US Native American and Hispanic, especially Mexican, populations.

Sex

A substantial female predominance exists worldwide, with female-to-male ratios of approximately 2.5:1 to 3:1.

Age

Gallbladder cancer is most typically diagnosed in the seventh decade of life, with a median age of 62-66 years.

Clinical

History

The symptoms of gallbladder cancer overlap with the symptoms of gallstones and biliary colic. Abdominal pain may be of a more diffuse and persistent nature than the classic right upper quadrant pain of gallstone disease. Jaundice, anorexia, and weight loss often indicate more advanced disease.

Physical

  • Jaundice
  • Palpable mass in the right upper quadrant (Courvoisier sign, if this is due to a palpable gallbladder)
  • Periumbilical lymphadenopathy (Sister Mary Joseph nodes)
  • Left supraclavicular adenopathy (Virchow node)
  • Pelvic seeding: Mass is palpated on digital rectal examination (Blumer shelf).

Causes

See Pathophysiology. Associated conditions include the following:

  • Chronic gallstones
  • Calcification of the gallbladder (porcelain gallbladder) - 10-25% incidence of gallbladder cancer
  • Crohn ileocolitis
  • Ulcerative colitis
  • Occupational chemical exposure
  • Estrogens
  • Typhoid carriers
  • Anomalous pancreatobiliary duct junction
  • Gallbladder polyps

More on Gallbladder Cancer

Overview: Gallbladder Cancer
Differential Diagnoses & Workup: Gallbladder Cancer
Treatment & Medication: Gallbladder Cancer
Follow-up: Gallbladder Cancer
References
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Further Reading

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Keywords

biliary cancer, biliary tract cancer, cancer of the biliary tree, gallbladder cancer, gallstones, cholesterol gallstones, chronic typhoid infections, abnormal pancreaticobiliary duct junctions, inflammatory bowel disease, IBD, polyposis coli, cholangiocarcinomas, primary sclerosing cholangitis, ulcerative colitis, liver flukes, chronic Salmonella typhi and paratyphi infections, and Helicobacter infection, Gardner syndrome, neurofibromatosis type I, hereditary nonpolyposis colon cancer, obesity, oral contraceptives, INH, isoniazid, methyldopa, chemical exposures, pesticides, rubber, vinyl chloride, occupational exposures, textile worker, petroleum worker, paper mill worker, shoemaker, water pollution, organopesticides, dichlorodiphenyltrichloroethane, benzene hexachloride, heavy metals, cadmium, chromium, lead, radiation exposure, radon in miners, apolipoprotein B gene, cytochrome P450 1A1 gene, CYP1A1, abdominal pain

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Contributor Information and Disclosures

Author

Mary Denshaw-Burke, MD, FACP, Assistant Clinical Professor, Department of Medicine, Thomas Jefferson University School of Medicine; Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Hospital; Consulting Staff, Lankenau Hospital, Delaware County Memorial Hospital, Mercy Fitzgerald Hospital, Bryn Mawr Hospital, Taylor Hospital
Mary Denshaw-Burke, MD, FACP is a member of the following medical societies: American College of Physicians
Disclosure: Sharpe-Strumia Fund at Bryn Mawr  Grant/research funds Other

Coauthor(s)

Jessica B Katz, MD, PhD, FACP, Hematology/Oncology Fellowship, Lankenau Hospital; Churchman Fellow, Lankenau Institute of Medical Research
Jessica B Katz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians and Phi Beta Kappa
Disclosure: Nothing to disclose.

Andrew Scott Kennedy, MD, Co-Medical Director, Wake Radiology Oncology
Andrew Scott Kennedy, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American Hepato-Pancreato-Biliary Association, American Society for Therapeutic Radiology and Oncology, American Society of Clinical Oncology, and Radiological Society of North America
Disclosure: Nothing to disclose.

David Van Echo, MD, Head, New Drug Development Program (Oncology), Professor, Departments of Medicine and Pharmacy, University of Maryland School of Medicine; Director of HarborView Cancer Center
Disclosure: Nothing to disclose.

Medical Editor

Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri at Columbia/Ellis Fischel Cancer Center
Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Hematology, Missouri State Medical Association, Southern Association for Oncology, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Hematology and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting

 
 
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