Gallbladder Cancer: The Basics

Neha Vapiwala, MD
Modified By: Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: March 20, 2012

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What is the gallbladder, and what does it do?

The gall bladder is a small pear-shaped organ that stores and concentrates a substance called bile. Bile is a greenish liquid substance produced by the cells of the liver (hepatocytes) that aids in the digestion of fats. It emulsifies fats, causing the fats to accumulate into droplets, which can be easily absorbed in the small intestine. It also aids in the absorption of so-called "fat soluble vitamins, such as vitamins A, D, E and K. Bile is also the way the body disposes of hemoglobin from old red blood cells which are no longer functional. This is what makes bile green and stool brown. Once hepatocytes (liver cells) have produced bile, it is transported to the duodenum (the segment of small intestine right after the stomach) via the common bile duct, where it is secreted through a small opening known as the Ampulla of Vater. It can then form droplets together with fat particles exiting the stomach. The bile also goes to the gallbladder where it can be stored. The gallbladder and liver are connected by the hepatic duct.

When you eat fatty food, the food passes from the stomach into the small intestine, and triggers the lining of the small bowel to release a hormone called CCK (cholecystokinin). CCK is then carried in the bloodstream to the gallbladder, where it causes the gallbladder to contract and send bile through the common bile duct and into the small bowel (duodenum). Gallstones form when the substances contained in bile crystallize into small, hard rocks.

How common is gallbladder cancer?

Primary cancer of the gallbladder is very rare and affects about 5000 adults in the US each year.

What are the types of gallbladder cancer?

The majority of these cancers are "adenocarcinomas" (named for the type of cell the cancer affects), with subtypes such as papillary, nodular, and tubular, depending on the appearance of the tumor cells under the microscope. Less common subtypes include: squamous cell, signet ring cell, and adenosquamous (adenoacanthoma).

Who gets gallbladder cancer?

Gallbladder cancer is most often seen in older patients, with a median age at diagnosis of 62-66 years. It occurs more often in females, with a female-to-male ratio of about 3:1. The highest rates of gallbladder cancer occur among US Native Americans, as well as in Mexico, South America, Israel, and China. In fact, Israel has the highest worldwide incidence, with 7.5 cases per 100,000 men and 13.8 cases per 100,000 women. Gallbladder cancer is the fifth most common GI cancer in the United States. However, it is the most common GI malignancy in Mexican Americans and Southwest Native Americans. Low rates are seen in India, Nigeria, and Singapore.

What causes gallbladder cancer? What are the risk factors?

The cause of gallbladder cancer is unknown, although it has been associated with gallstones, high estrogen levels, cigarette smoking, alcohol, obesity, and the female gender. Approximately 70-90 percent of people with gallbladder cancer have gallstones. However, the opposite is not true, as most people with gallstones do not develop gallbladder cancers, and it is unclear how big of a risk gallstones pose. It has been suggested that infection with salmonella may increase the risk of gallbladder cancers. Patients with inflammatory bowel disease (ulcerative colitis and Crohn's disease) are 10 times more likely to develop cancer of the extrahepatic biliary tract.

What are the signs and symptoms of gallbladder cancer?

Unfortunately, there are no specific, surefire symptoms that suggest a diagnosis of gallbladder cancer. Typically, patients present with problems resulting from blockage of the bile ducts, such as jaundice, loss of appetite and weight loss. There may be a mass and/or pain in the abdomen, especially on the right under the ribcage. However, people often have no symptoms, or their symptoms closely mimic those of gallstones. The most common way gallbladder tumors are diagnosed is incidentally, during surgery performed to remove the gallbladder (cholecystectomy) for some other reason. About 1-2% cholecystectomies reveal a cancer of the gallbladder.

On patient examination, a healthcare provider (HCP) may detect jaundice (yellowing) of skin or the whites of the eyes, a mass in the right upper abdominal quadrant or around the belly button (periumbilical).

How is gallbladder cancer diagnosed?

First and foremost, a HCP should always perform a thorough history and physical examination. Laboratory work should include metabolic chemistry and liver function panels to look for abnormal levels of various substances in the blood that are suggestive of general hepatobiliary disease. A urinalysis is usually done to evaluate urinary levels of some of these substances as well.

*The role of tumor markers, [carbohydrate antigen 19-9 (CA 19-9), cancer antigen 125 (CA125), and carcinoembryonic antigen (CEA)] has not been established in gallbladder cancer.

Ultrasonography (US) is the standard study done first in patients presenting with right upper quadrant pain. It allows HCPs to make a diagnosis of gallbladder cancer in about half of patients, and can also detect disease spread into the liver or bile ducts about half of the time. This is an important test, as it can help differentiate people who are having pain from gallstones from those who have gallbladder cancer. Endoscopic ultrasound, where a camera is inserted down through the mouth (while under sedation) allows the ultrasound probe to be placed closer to the gallbladder and appears to be more accurate than the traditional ultrasound which is placed against the abdominal wall. Endoscopic ultrasound may also better detect nodes and whether the tumor has spread beyond the gallbladder.

Computed tomography (CT) scans can also be helpful in patients with upper abdominal pain. They are better than US for detecting tumor invasion out of the gallbladder and disease spread to other sites in the abdomen or pelvis. About 70-80% of cases will have some degree of liver invasion, and so the combination of CT and US provides more accurate information.

Magnetic resonance imaging (MRI) has been useful in examining this region for disease spread into the liver or other tissues. This technology is particularly good for planning surgery, by evaluating surrounding blood vessels [magnetic resonance angiogram (MRA)] and bile duct passages [magnetic resonance cholangiogram (MRC)].

Cholangiography, either through the skin or the stomach, is a technique that allows HCPs to not only establish a diagnosis, but to locate a blockage and place a stent through the blockage to help alleviate the blockage.

Routine blood work may also help your physician determine whether there is a blockage in the bile ducts and how well the liver is functioning. There are tumor markers, which can be tested for in the blood, such as CEA and CA 19-9. These markers can be elevated in cancer of the gallbladder, but are not good for diagnosis as they are non-specific and other conditions can cause them to be elevated.

How is gallbladder cancer staged?

The American Joint Committee on Cancer uses the TNM system to stage gallbladder cancer as follows: (Adapted from AJCC 7 th edition, 2010)

Primary tumor (T)

  • TX - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • Tis - Carcinoma in situ
  • T1a - Tumor invades mucosa
  • T1b - Tumor invades muscle layer
  • T2 - Tumor invades perimuscular connective tissue
  • T3 - Tumor invades/perforates the serosa and/or directly invades the liver and/or one other adjacent organ or structure
  • T4 - Tumor invades main portal vein or hepatic artery or multiple adjacent organs

Regional lymph node (N)

  • NX - Regional lymph nodes cannot be assessed
  • N0 - No metastases in regional lymph nodes
  • N1 - Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein
  • N2 - Metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes

Metastases (M)

  • MX - Presence of metastases cannot be assessed
  • M0 - No distant metastases
  • M1 - Distant metastases

TNM Groupings by Stage

The above T, N & M are then combined to come up with a stage.

 

Stage

T (Tumor Size)

N (lymph Nodes)

M (Metastasis)

Stage 0

Tis

N0

M0

Stage IA

TI

N0

M0

Stage II

T2

N0

M0

Stage IIIA

T3

N0

M0

Stage IIIB

T1

N1

M0

 

T2

N1

M0

 

T3

N1

M0

Stage IVA

T4

N0-1

M0

Stage IVB

Any T

N2

M0

 

Any T

Any N

M1

How is gallbladder cancer treated?

As with many tumor types, management is often a multidisciplinary approach involving a variety of treatments.

Surgery

For early stage disease (Stage IA), surgery alone is considered curative. In patients who have a gallbladder cancer found during a cholecystectomy, reexcision is recommended if the disease is stage II or higher. In stage IB disease, the need for reexcision is more controversial, but usually recommended. Total surgical removal of all known tumor is the only truly "curative" treatment. Unfortunately, only about 10-25% of patients with gallbladder cancer are able to undergo total surgical removal. Furthermore, such a procedure is typically quite extensive, and involves removal of the gallbladder, regional lymph nodes, and a portion of liver if there is concern of invasion. As you might expect, such a surgery carries a high risk of serious complications. Even when surgery is possible, the surgeon is usually unable to take very large resection margins around the tumor, meaning that cancer cells may exist at, or very close to, the tissue edges where the surgeon cut. Even with improving surgical techniques, the risk of recurrence is high. In such cases, external beam radiation therapy can be used in hopes of eradicating any microscopic cancer remaining in the surgical area and surrounding at-risk regions. Median survival in patients with advanced but operable disease is roughly 12 months in those with positive margins (and can sometimes be improved to over 16 months with postoperative radiation therapy), but up to several years in those with negative margins.

Chemotherapy and Radiation

For patients who are unable to undergo surgery, either because the disease is too advanced or because of other serious medical conditions, radiation therapy can be used with or without chemotherapy in order to improve symptoms, and in some cases, increase survival. Radiation usually targets the tumor (or tumor bed, if post-surgery) and the lymph nodes in that area.

Adjuvant chemotherapy (chemotherapy given after surgery) can also be considered, most commonly with 5-FU or gemcitabine, combined with cisplatin or oxaliplatin. There are small single institutional reports of adjuvant chemoradiation (both chemotherapy and radiation given after surgery), and this treatment paradigm has resulted in five year survival ranging from 30 to 60%,

In advanced cases, chemotherapy may be used alone. A randomized phase III trial comparing gemcitabine plus cisplatin vs. gemcitabine alone in 400 patients with advanced or metastatic biliary tract tumors (including 150 with gall bladder cancers) has recently been reported. The addition of cisplatin to gemcitabine resulted in a longer progression-free survival (PFS); 8.4 months compared to 6.5 months for gemcitabine alone. At present, there are several trials investigating various combinations of chemotherapy

What are the outcomes of treatment?

Disease stage at presentation is the most important prognostic factor.

Stage I patients can have very good 5-year survival rates, on the order of 70-85% after a complete surgery. Perioperative mortality rates range from 0-21%, depending upon the extent of liver resection required or the need for pancreas and small bowel removal (pancreaticoduodenectomy).

5-year survival rates

  • stage I - 70-85%
  • stage II - 25%
  • stage III - 12%
  • stage IV - 1-2%

References and Further Reading

NCI General Information About Gall Bladder Cancer

American Cancer Society: Cancer Facts and Figures 2012.

Baeza MR, Reyes-Vidal JM, del Castillo C. Post-operative adjuvant radiochemotherapy in the treatment of gallbladder cancer. Int J Radiat Oncol Biol Phys. 2005;63:S285–S86

Czito B, Hurwitz H, Clough R, et al. Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys. 2005;62: 1030–4.

Kresl J, Schild S, Henning G, et al. Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys. 2002;52:167–75.

Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 211-7.

Hueman, MT. Vollmer, CM Jr. Pawlik, TM. Evolving Treatment Strategies for Gallbladder Cancer. Annals of Surgical Oncology. 16(8):2101-15, 2009 Aug.

Valle JW, Wasan HS, Palmer DD et al. Gemcitabine with or without cisplatin in patients (pts) with advanced or metastatic biliary tract cancer (ABC): Results of a multicenter, randomized phase III trial (the UK ABC-02 trial). J Clin Oncol 2009;27(15 suppl):4503.

Zhu, AX et al. Current Management of Gallbladder Carcinoma. The Oncologist 15(2):168-181. 2010.


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