Gallbladder Cancer

Updated: Jun 28, 2017
  • Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Overview

Practice Essentials

Gallbladder cancer is a rare disease that often arises in the setting of chronic inflammation. The American Cancer Society estimates that approximately 11,740 new cases of gallbladder cancer and other biliary cancers will be diagnosed in 2017. [1]

The image below is a schematic drawing of the extent of lymphadenectomy for gallbladder cancer.

A schematic drawing of the extent of lymphadenecto A schematic drawing of the extent of lymphadenectomy for gallbladder cancer, especially when the extrahepatic biliary tree is resected.

Signs and symptoms

Signs and symptoms are usually not present until the later stages of gallbladder cancer and may include the following:

  • Jaundice
  • Pain above the stomach
  • Fever
  • Nausea and vomiting
  • Bloating
  • Lumps in the abdomen

Jaundice, anorexia, and weight loss often indicate more advanced disease.

See Presentation for more detail.

Diagnosis

Gallbladder cancer is difficult to detect and diagnose. Signs and symptoms are not usually seen in the early stages of disease and often overlap with the symptoms of gallstones and biliary colic.

Laboratory studies

Some tests that may prove helpful in diagnosing gallbladder cancer include the following:

  • Liver function tests
  • CA 19-9 assay
  • Carcinoembryonic antigen (CEA) assay

Imaging studies

Ultrasonography (US) is a standard initial study in patients with right upper quadrant pain. A mass can be identified in 50-75% of patients with gallbladder cancer.

Computed tomography (CT) scans also may be useful in patients with upper abdominal pain and can demonstrate tumor invasion outside of the gallbladder and identify metastatic disease elsewhere in the abdomen or pelvis.

Percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiography (ERCP) may establish the diagnosis of gallbladder cancer by bile cytology. Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive way to take images of the bile ducts using the same type of machine used for standard MRI scans.

Staging

The following stages are used for gallbladder cancer:

  • Stage 0 (carcinoma in Situ) : Abnormal cells are found in the inner (mucosal) layer of the gallbladder; these abnormal cells may become cancer and spread into nearby normal tissue [#Keypoint11]
  • Stage I : Cancer has formed and has spread beyond the inner (mucosal) layer to a layer of tissue with blood vessels or to the muscle layer
  • Stage II : Cancer has spread beyond the muscle layer to the connective tissue around the muscle.
  • Stage IIIA : Cancer has spread through the thin layers of tissue that cover the gallbladder and/or to the liver and/or to one nearby organ (eg, stomach, small intestine, colon, pancreas, or bile ducts outside the liver)
  • Stage IIIB : Cancer has spread to nearby lymph nodes and beyond the inner layer of the gallbladder to a layer of tissue with blood vessels or to the muscle layer; or beyond the muscle layer to the connective tissue around the muscle; or through the thin layers of tissue that cover the gallbladder and/or to the liver and/or to one nearby organ
  • Stage IVA : Cancer has spread to a main blood vessel of the liver or to 2 or more nearby organs or areas other than the liver. Cancer may have spread to nearby lymph nodes.
  • Stage IVB : Cancer has spread to either lymph nodes along large arteries in the abdomen and/or near the lower part of the backbone or to organs or areas far away from the gallbladder.

See Workup for more detail.

Management

The main types of treatments used for gallbladder cancer include the following:

  • Surgery
  • Radiation therapy
  • Chemotherapy
  • Palliative therapy

Although complete surgical resection is the only therapy to afford a chance of cure, en bloc resections of the gallbladder and portal lymph nodes carry a high morbidity and mortality (similar to bile duct carcinoma). Nodal metastases outside of the regional area (ie, porta hepatis, gastrohepatic ligament, retroduodenal area) are not resectable.

See Treatment and Medication for more detail.

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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 gastrointestinal (GI) cancer in the United States. [2] Worldwide, it is the sixth most common GI cancer and the most common biliary tract malignancy, accounting for 80%–95% of biliary tract cancers. [3] About 20% arise from the extrahepatic biliary tract and 20% arise from the ampulla of Vater. [4] Despite some similarities, gallbladder cancer is a distinct clinical entity and will be discussed exclusively in this article.

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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. [5] Other more unusual causes of chronic inflammation are also associated with gallbladder cancer. These causes include primary sclerosing cholangitis, ulcerative colitis, [6] liver flukes, chronic Salmonella typhi and paratyphi infections, [7] and Helicobacter infection. [8]

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. Obesity [9] 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 alargenumberofinflammatorymediators. [4]

An increased incidence of gallbladder cancer also occurs in hereditary syndromes including the following [4] :

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. [10] Another study looked at polymorphisms within the apolipoprotein B gene. [11]

A case-control genome-wide association study from India identified common genetic variations that confer gallbladder cancer risk at genome-wide significance. Substantial variation in risk was associated with single-nucleotide polymorphisms involving the hepatobiliary phospholipid transporter genes ABCB1 and ABCB4, suggesting a role for those genes in the pathology of gallbladder cancer. [12]

Wu et al retrospectively analyzed surgical specimens from 97 consecutive gallbladder cancer patients treated in Taiwan between 1993 and 2005 at 2 tertiary medical centers for alpha-methylacyl coenzyme A racemase (AMACR) expression. The authors found that overexpression of this enzyme in gallbladder cancer was associated with a more advanced T stage, a higher histologic grade and vascular invasion. Overexpression of AMACR was also found to be an independent predictor of decreased disease-specific survival in this group of patients. [13]

Abnormal anatomy such as congenital defects with anomalous pancreaticobiliary duct junctions and choledochal cysts increase the risk of gallbladder cancer. [14, 15] 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. In addition, approximately 50% of patients have regional lymph node metastases.

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

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Frequency

United States

Gallbladder cancer incidence increases with age and is more common in women. Approximately 11,740 new cases of gallbladder cancer and other biliary cancers are predicted for 2017, according to the American Cancer Society—5320 in men and 6420 in women. Approximately 3830 deaths are projected for 2017, 1630 in men and 2200 in women. [1]

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. [4] 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. [1] 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. [4]

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%. [1]

International

Considerable variation exists in the incidence of gallbladder cancer throughout the world. Areas with the highest incidence rates include India, Korea, Japan, Czech Republic, 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. Women 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. [4, 7] The United Kingdom, Denmark, and Norway have the lowest international incidence rates. Gallbladder cancer is the most common cancer affecting women in Chile.

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Mortality/Morbidity

Survival is correlated with staging based on the American Joint Committee on Cancer (AJCC) tumor, node, metastases (TNM) staging system. [16] 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%. [4]

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%. [3] 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-, sex-, and age-related demographics

The highest rates of gallbladder cancer in the US are found in the US Native American and Hispanic, especially Mexican, populations. A substantial female predominance exists in the US and worldwide, with female-to-male ratios of approximately 2.5:1 to 3:1. Gallbladder cancer is most typically diagnosed in the seventh decade of life, with a median age of 62-66 years.

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