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Gallbladder cancer: lessons from a rare tumour

Key Points

  • Gallbladder cancer is a relatively rare neoplasm worldwide, but shows significant geographic variation in incidence, being particularly common in certain native American populations. The prognosis for patients with this neoplasm is poor, as diagnosis is often at late, untreatable stages of the disease.

  • A unique combination of predisposing factors makes gallbladder carcinoma a unique tumour and offers potential for understanding cancer pathogenesis. These factors include ethnicity, genetic predisposition, geographic location, female gender, chronic inflammation and congenital developmental abnormalities.

  • Two main pathways of gallbladder carcinoma pathogenesis have been identified. The most common is associated with gallstones and chronic inflammation of the gallbladder, whereas a second, less frequent pathway is associated with a congenital abnormality of the pancreatic bile-duct junction, which is particularly common in Japan.

  • A multistage sequence of histopathological and molecular changes has been identified for gallbladder carcinoma, which is especially well-defined for tumorigenesis associated with gallstones. Molecular abnormalities commence in normal-appearing epithelium in chronically inflamed gallbladders.

  • TP53 inactivation has an important and early role in gallbladder carcinoma associated with gallstones and chronic inflammation. Different patterns of TP53 mutation have been detected in the two main types of gallbladder carcinomas that have been identified.

  • Although KRAS mutations are rarely detected in gallbladder carcinomas associated with gallstones, they are frequent and early events in tumours associated with congenital abnormality of the pancreatic bile-duct junction.

  • Relatively little is known about gallbladder cancer, and a significant influx of research funding is required for this to be remedied. In particular, the identification of susceptibility genes, elucidation of the role of inflammation and an increased understanding of the molecular changes that occur during multistage pathogenesis should be important goals for the future.

Abstract

Gallbladder cancer is a relatively rare form of malignancy about which our knowledge is scant. However, a unique combination of predisposing factors — including genetic predisposition, geographic distribution, female gender bias, chronic inflammation and congenital developmental abnormalities — makes this type of cancer unique and offers potential for understanding cancer pathogenesis in general. An understanding of how these risk factors contribute to the molecular basis of the disease is essential for understanding the origins of this unusual cancer.

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Figure 1: The human biliary system.
Figure 2: Worldwide incidence of gallbladder carcinoma.
Figure 3: Female gender bias in GBC occurrence.
Figure 4: Two pathways involved in the pathogenesis of gallbladder carcinoma.
Figure 5: Sequential histopathological and molecular changes in the pathogenesis of gallbladder carcinoma associated with gallstones and inflammation.

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Acknowledgements

Work in the authors laboratory is supported by grants from FONDECYT (Fondo Nacional de Desarrollo Cientifico y Tecnologico Chile) and the Early Detection Research Network, National Cancer Institute. We thank I. Roa for his assistance with the histopathology pictures in figure 5.

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Correspondence to Adi F. Gazdar.

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DATABASES

Cancer.gov

bladder cancer

cervical cancer

colorectal cancer

gallbladder cancer

gastric cancer

liver cancer

lung cancer

oesophageal cancer

ovarian cancer

Entrez Gene

CDKN1A

COX2

ERBB2

FHIT

INK4A

KRAS

RB

TP53

FURTHER INFORMATION

TP53 mutation database

Glossary

CHOLECYSTECTOMY

Surgical removal of the gallbladder.

CHRONIC CHOLECYSTITIS

Chronic inflammation of the gallbladder wall that is almost always associated with the presence of gallstones and is thought to result from repeated bouts of acute or subacute cholecystitis.

MICELLE

A globule of lipid molecules in water where the non-polar ends face inward and the polar tails face outward.

MAPUCHE INDIANS

The main American Indian tribe of Chile, which has very high incidences of cholelithiasis and gallbladder cancer. Much of our knowledge of gallbladder cancer is derived from studying this subpopulation.

ODDS RATIO

The odds of developing a particular disease in the exposed group divided by the odds of developing it in an unexposed group. Usually derived from a case–control study.

LITHOGENIC GENES

Genes associated with an increased incidence of gallstone formation and, directly or indirectly, of gallbladder cancer.

CALCIUM BILIRUBINATE

A salt composed of calcium and insoluble bilirrubin that results in the precipitation of pigmented gallstones.

HYPERLIPIDAEMIA

General term for increased concentrations of any or all of the lipids in the plasma, such as cholesterol, triglycerides and lipoproteins.

GALLBLADDER HYPOMOTILITY

A reduction in the contractile activity of the gallbladder required to evacuate bile content into the duodenum.

STASIS

Accumulation of bile content of the gallbladder producing dilatation and an increase in bile viscosity.

ACUTE CHOLECYSTITIS

Acute inflammation of the gallbladder wall that can be evoked by mechanical, chemical or bacterial factors.

DYSPLASIA

An epithelial change that frequently precedes the development of invasive carcinoma. It is characterized by mild to severe cytological and structural abnormalities.

CARCINOMA IN SITU

Pre-invasive epithelial precursor of invasive carcinomas, without disruption of the basement membrane and characterized by severe cytological changes, similar to those detected in the invasive counterpart.

HYPERCHROMATIC

Showing dark staining of the nucleus, indicating increased chromatin content.

ALLELOTYPING STUDIES

Analyses of loss of heterozygosity (LOH) — a hallmark of tumour-suppressor-gene inactivation — that is performed using microsatellite markers.

MICROSATELLITE MARKERS

Polymorphic tandem-repeat sequences distributed throughout the genome that have been used to detect loss of heterozygosity.

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Wistuba, I., Gazdar, A. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer 4, 695–706 (2004). https://doi.org/10.1038/nrc1429

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