Since gallstones are common in western populations, they will often be found by chance in people who present with abdominal pain caused by other factors such as cancer. It is well established that early manifestations of abdominal cancer are sometimes misdiagnosed as gallstones and treated with cholecystectomy. For example, recent studies have shown that, of patients readmitted within a few months of laparoscopic cholecystectomy, a common cause of readmission is colon cancer (Gal et al, 1998
; Malouf et al, 2000
; Wysocki et al, 2001
The literature on whether there is a causal association between cholecystectomy and colon cancer is inconsistent. It is clear, however, that the most markedly positive association has come from the studies with designs that are most susceptible to bias. The choice of controls may influence the results of case–control studies and cohort studies with long-term follow-up are more satisfactory. In 1993, Giovannucci et al (1993)
published a meta-analysis of 33 case-cohort and 6 cohort studies. The pooled results from the 33 case–control studies showed a significant positive association between cholecystectomy and colorectal cancer (relative risk (RR) 1.34, 95% confidence interval 1.14–1.57). If, however, there are systematic biases in such studies that tended to go in the same direction, pooling the studies will simply combine the biased findings. The meta-analysis found no significant association between cholecystectomy and colon cancer in the combined results from the six cohort studies (RR 0.97, 0.82–1.14; Giovannucci et al, 1993
). Another meta-analysis has since reported very similar findings (Reid et al, 1996
), while three more large cohort studies with long follow-up have also reported on the subject. A study from Sweden (Lagergren et al, 2001
) updating previous Swedish studies (Adami et al, 1987
; Ekbom et al, 1993
) reported a significant but small increase in risk of intestinal cancer after cholecystectomy. A study from Holland with relatively few cancers reported an increased risk of colorectal cancer (Goldbohm et al, 1993
). A US study of 85
184 women followed for 16 years reported a non-significant increase in the risk of colon cancer overall after cholecystectomy, with the highest risk in the proximal colon at the shortest reported time (of less than 5 years) interval after the operation (Schernhammer et al, 2003
). This study also reported a significant increase in cancer of the rectum. The results of these three as well as the previous cohort studies have not removed uncertainty about any causal association between cholecystectomy and colon cancer. Other cancers, too, have been studied after cholecystectomy, but the evidence on causality associations with cancers of the pancreas, liver, and stomach is also inconsistent (Ekbom et al, 1996
; Johansen et al, 1996
; Chow et al, 1999
; Schernhammer et al, 2002
The strengths of our study are that it is a large cohort study; records of cholecystectomy and of cancer were created independently and only subsequently brought together; it examines different time intervals from operation to cancer, with many cases of cancer at long time intervals after operation; and it was undertaken in a geographically defined, but otherwise unselected, population. Most forms of bias that can occur in case–control studies – such as selection, referral, or responder bias – are unlikely or impossible in a population-based cohort study.
The study has some weaknesses. We have no information about the criteria used for cancer diagnosis, or about when, prior to admission for cancer, this diagnosis was first suspected or made. The database of hospital records is confined to hospital inpatients or to day cases, which we believe would identify all cases of cholecystectomy, and the great majority of cancer cases would be identified by these sources. We do not have records of admission or death in people who migrated out of the area after cholecystectomy or after admission for the reference conditions. We assumed that outward migration is not appreciably different in the cholecystectomy and reference cohorts. The fact that the rate ratios shown in the are generally close to one, both for those cancers where there was a prior hypothesis about an association and for those cancers outside the gastrointestinal tract where there was not, suggests that the reference cohort is not materially biased with respect to migration. If it were, cancer rates in general would have been systematically high or low. It also suggests, more generally, that the reference cohort is an appropriate comparator with respect to its composition. We consider that the slight deficit of breast cancer in association with cholecystectomy, although statistically significant, is probably due to chance.
We found significantly elevated rates of several intra-abdominal cancers overall but, after excluding cancers within 2 years of cholecystectomy, there was no elevation of rates, making it very unlikely that these associations are causal. The rate ratios of cancers in the cholecystectomy cohort, compared with the reference cohort, did not increase with time from operation. Our findings add to the evidence that cholecystectomy probably does not cause cancer.