Review
Cholelithiasis in gallbladder cancer: Coincidence, cofactor, or cause!

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Abstract

Background

While gallstones are associated with cancers of the gallbladder, the actual nature of their relationship needs to be clarified. This would aid the recommendations on the need for prophylactic cholecystectomy.

Methods

A systematic search of the scientific literature was carried out using the Medline, the Embase, and the Cochrane Central Register of Controlled Trials for the years 1891–2009 to obtain access to all publications involving gallstones in gallbladder cancer.

Results

While some epidemiological evidence supports a causal relationship for gallstones in gallbladder cancer, other studies have demonstrated a relatively low incidence of gallbladder cancer in countries reporting a high incidence of gallstones as a whole. In those studies where gallstones appear to have a causative role for cancer, the risk increases with increasing size, volume and weight, and number of the stones. The impact of duration of the stone or its composition is not clear. Experimental evidence from studies examining the impact of artificially introducing gallstones in the gallbladder has failed to lead to carcinogenesis.

Conclusions

The evidence at the current time indicates that gallstones are a cofactor in the causation of gallbladder cancer. Absolute proof of their role as a cause for gallbladder cancer is lacking. The recommendation for prophylactic cholecystectomy in countries reporting a high incidence of gallbladder cancer and associated gallstones needs to be tailored to the epidemiological profile of the place.

Introduction

While the presence of gallstones with gallbladder cancer has been appreciated since the 19th century,1, 2 the cause–effect relationship is a matter of debate. Do we consider the gallstone to be an innocent bystander, a contributory factor, or a cause for gallbladder cancer?!

The apparent urgency to answer the question on the association of gallstones and gallbladder cancer stems from the fact that gallbladder cancer is a disease with a poor outcome and should we able to demonstrate the causal relationship of gallstones to gallbladder cancer, we would place ourselves in a position to offer cholecystectomy for gallstones as a preventative measure against the cancer.

Reviewing the literature to answer the question on the nature of the association of gallstones and gallbladder cancer is not easy. This is because there are numerous points that need to be addressed on gallstones which include the following:

  • 1)

    What is the strength of the epidemiological association between gallstones and gallbladder cancer?

  • 2)

    Does the duration for which the patient has the gallstone play a role in the pathogenesis of cancer?

  • 3)

    Do the size, weight and volume of the gallstone affect its ability to influence cancer development?

  • 4)

    Does the number or type of gallstone play a role in cancer causation?

Section snippets

Methods

In an attempt to answer these questions, a systematic search of the scientific literature was carried out using the Medline, the Embase, and the Cochrane Central Register of Controlled Trials for the years 1891–2009 to obtain access to all publications involving gallstones in gallbladder cancer.

The search strategy was that described by Dickersin and colleagues3 with the appropriate specific search terms ‘gallstones’, ‘cholelithiasis’, ‘and gallbladder cancer’ looking for studies linking

Results

The adopted search strategy revealed 1570 articles of which 1526 were excluded for lack of clear data relating to gallstones and gallbladder cancer. Of the remaining 44 articles included in the study, 26 articles which provided clear epidemiological evidence of the relationship of gallstones to gallbladder cancer were then specifically analysed.

Discussion

Gallstones have been found to be associated with gallbladder cancer in varying frequency. This is dependent on the location of the study, with some studies reporting a high coexistence of the two entities,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 40, 41 while others have suggested fairly modest figures of 30–60%.42, 43, 44, 45 And while there is substantial epidemiological data to support the role of gallstones in gallbladder cancer (Table 1), very often the

Conclusions

Gallstones have traditionally been regarded as an aetiological factor for gallbladder cancer. Despite some epidemiological data to support this, experimental models have failed to replicate the carcinogenetic process. It is thus difficult at the present time to firmly conclude whether gallstones are the cause or mere innocent by-standers in the causation of gallbladder cancer. They may however, be regarded as cofactors. In light of the high incidence of gallstones in regions reporting

Conflict of interest

We declare no conflicts of interest.

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