Gallbladder Cancer

This section relies heavily on the WHO Cancer Pathology chapter on the Gallbladder, and on UpToDate


The incidence of gallbladder cancer around the world is highly variable between countries and between ethnic groups in the same country. In all groups, they are significantly more common in women than men - most likely due to the higher prevalence of gallstones in women. They are usually describes as the fifth most common gastrointestinal malignancy.

  • Australian data is difficult to find as liver and gallbladder malignancies are typically grouped together
  • There is an increased rate of gallbladder cancer in Indigenous Australians
  • In the United States, gallbladder cancer accounts for 0.17% of cancers in men and 0.49% in women
  • In the United States, the incidence is 21 per 100,000 in female Native Americans versus 1.4 per 100,000 in white Americans

Gallbladder cancer is typically a disease of people over the age of 60.

Aetiology and Pathogenesis

There are several risk factors associated with increased rates of gallbladder carcinoma:

  • Gallstones are present in 95% of people with gallbladder cancer; however the incidence of gallbladder cancer in people with gallstones is very low (0.5% or less). Gallstones increase the risk of gallbladder cancer by 34 times compared to a stoneless population. This most likely explains the elevated risks in female and obese populations.
  • Chronic gallbladder infection with Salmonella typhi or Helicobacter is thought to be an important factor in some geographical areas; S. typhi infection with the presence of gallstones confers a 14 fold increase in risk compared to gallstones alone.
  • Variations of the pancreatic and common bile duct junctions may occur. Rarely, the two ducts may unite up to 2 cm from the sphincter. This may allow pancreatic secretions to enter the biliary tree more easily, leading to hyperplasia and dysplasia of the epithelium.
  • Porcelain gallbladder (calcification of the gallbladder wall) is strongly associated with malignancy, which is present in 10 - 25% of cases


There are two major routes through which pathogenesis of gallbladder cancer may occur:

  • Chronic inflammation due to gallstones is the most common aetiology in the Western world. Inflammation can act as both an initiator and promoter.
    • In some parts of the world, chronic infection due to Salmonella typhi is also indicated
  • Reflux of pancreatic secretions is a much rarer cause and is due to an abnormal junction of the pancreatic and common bile ducts. This leads to hyperplasia of the gallbladder epithelium, which eventually leads to dysplasia with repeated stimulus.

Natural History

Multistep carcinogenesis is thought to occur in the gallbladder, with progression from dysplasia to carcinoma in situ and eventually invasive cancer. The time for progression from dysplasia to malignancy, on average, about 15 years. Even if treated, five year survival is under 10%.
The tumour effects include:

  • local invasion into adjacent structures, such as the liver, duodenum or large bowel.
  • regional nodes involvement, particularly in the hilum of the liver, the nodes about the pancreas and duodenum, and the superior mesenteric or coeliac nodes.
  • distant metastasis usually occurs to the liver and peritoneum, and sometimes to lung and pleura.

It is common for the disease to be advanced when first symptomatic. Most early cases are found serendipitously.

Clinical Presentation

UpToDate describes four common presentations:

  • Incidental finding on pathological examination of the gallbladder following cholecystectomy
  • Incidental finding during cholecystectomy
  • Suspected malignancy due to symptoms and imaging findings
  • Incidental finding on imaging

Symptoms & Signs

Patients may be asymptomatic or symptomatic. Asymptomatic patients are more likely to have localised disease. Symptoms, if present, are similar to that of cholecystitis, with right upper quadrant pain, nausea, vomiting and anorexia. Advanced disease may present with jaundice.


Ultrasound is the staple investigation for gallbladder diseases. It is limited in its detection of gallbladder cancer (< 40% accuracy). Endoscopic ultrasound provides significantly greater accuracy at the expense of a more invasive procedure.
CT and MRI scanning provides increased anatomical detail, and MRI is capable of distinguishing between benign and malignant polyps.
Laboratory investigations are unhelpful for diagnosis. Elevated cholestatic enzymes (GGT/ALP) may be present, and CEA is also elevated in some cases.

Tumour/Normal Tissue Features

Macroscopic features

Gallbladder tumours are typically grey-white and have two growth patterns.

  • Infiltrative tumours invade the wall of the gallbladder and appear as a thickened area (see arrows); they may involve the entire gallbladder wall at diagnosis
  • Papillary tumours grow exophytically and fill the gallbladder lumen; they have a better prognosis.
  • Imaging the smooth outline of the gall bladder will be lumpy, there maybe infiltration of the liver as the two lie together anteriorly.

Microscopic Features

Gallbladder tumours are adenocarcinomas in about 90% of cases, although variants may arise.

  • Adenocarcinoma with no other features accounts for about 76% of cases. These tumours show glandular differentiation and often contain mucin
    • Papillary adenocarcinoma accounts for 6% of cases; cells are arranged in papillae and may show intestinal differentiation
    • Adenocarcinoma with intestinal differentiation resembles the intestinal mucosa, with goblet cells
    • Mucinous adenocarcinoma, accounting for 5% of cases, is diagnosed when 50% or more of the tumour cells contain mucin.
    • Signet ring and clear cell carcinomas are both rare types of adenocarcinoma
  • Adenosquamous and squamous cell carcinomas are very rare in the gallbladder but have been reported
  • Small cell carcinoma is a neuroendocrine malignancy similar to small cell carcinomas elsewhere. They may spread extensively through the submucosa beyond an obvious lesion.
  • Undifferentiated carcinomas make up the rest of the epithelial malignancies

Lymphoma, sarcoma and other malignancies may also, very rarely, occur in the gallbladder.


The TNM staging system is the most commonly used method.

These guidelines are taken from the 7th Edition of the AJCC Cancer Staging Manual

Tumour Stage

  • TX - Primary tumour unable to be assessed
  • T0 - No evidence of primary tumour
  • Tis - Carcinoma in situ
  • T1 - Invasion of lamina propria (T1a) or muscular layer of gallbladder (T1b)
  • T2 - Invasion through muscle into surrounding connective tissue; no invasion of serosa/liver
  • T3 - Invasion:
    • Through the serosa, and/or
    • Into the liver, and/or
    • Into another adjacent organ
  • T4 - Invasion of portal vein, hepatic artery, or two or more non-hepatic organs

Nodal Stage

Regional nodes are divided according to their distance from the gallbladder; those around the porta hepatis are N1 and the more central nodes are N2.

  • NX - Unable to be assessed
  • N0 - No regional lymph node metastases
  • N1 - Metastases to nodes along the cystic duct, bile duct, hepatic artery or portal vein
  • N2 - Metastases to coeliac, superior mesenteric or lumbar lymph nodes (para-aortic/para-caval)

Distant Metastases

Much the same as other organ sites.

  • MX - Unable to be assessed
  • M0 - No distant metastases
  • M1 - Distant metastases

Overall Stage

  • Stage 0 is in situ disease - 80% 5 year survival
  • Stage I is T1 disease - 50% 5 year survival
  • Stage II is T2 disease - 30% 5 year survival
  • Stage III is subdivided: - <10% 5 year survival
    • IIIA is T3 with no nodes
    • IIIB is T1-3 with N1 nodes
  • Stage IV is subdivided - < 5% 5 year survival
    • IVA is T4 with N0 or N1 disease
    • IVB is N2 or M1 disease