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It is well accepted that patients with ulcerative colitis (UC) are at increased risk of developing colorectal carcinoma. Since 1992, several studies have examined the hypothesis that patients with concomitant primary sclerosing cholangitis (PSC) are at significantly increased risk of developing colorectal cancer or dysplasia. The size, design, end points, and populations involved in these studies have varied but critical review suggests that colorectal cancer is more common in the setting of PSC. Although the data do not allow exact quantification of the increased relative risk, there are nevertheless implications, both for understanding disease pathogenesis and for clinical practice.

An increased risk of developing colorectal carcinoma in patients with UC was first recognised in the 1920s.1 The magnitude of this risk varies in different studies with a range in cumulative risk after diagnosis in patients with pancolitis of between 1% and 3% at 10 years, 10% at 20 years, and 25% at 35 years.2-5 It is now widely accepted that risk factors for malignant transformation are duration of disease and extent of colitis. The presence of graded dysplasia6 or DNA aneuploidy within the colorectal mucosa, and an early age at onset have been described as additional risk factors.4 It has also been suggested that pharmacological therapy of colitis with sulphasalazine or mesalazine may be associated with a reduced incidence of neoplastic transformation.7 8

PSC is a disease of unknown aetiology characterised by cholestasis associated with diffuse inflammation and fibrosis of the entire biliary tract.9 PSC has a variable clinical course, progressing eventually to cirrhosis and premature death from hepatic failure. Furthermore, PSC is accompanied by a risk of developing carcinoma of the bile ducts.10

Although PSC may occur in isolation, it is closely associated with inflammatory bowel disease, in particular UC. Up to 80% of patients with PSC also have UC, usually with extensive or total colonic involvement.11 The prevalence of PSC in UC is much lower, with its occurrence related to the extent of disease. A population based study found a prevalence of 5.5% in patients with substantial colitis and of 0.5% in patients with distal colitis only,12 although these values are likely to underestimate the risk of PSC as not all patients with PSC have abnormal liver function tests.13

The concept that PSC is associated with an increased risk of colorectal neoplasia in patients with UC was proposed by Broomé et al in 1992.14 In a study of 17 patients with UC who were found to have dysplasia, carcinoma, and/or DNA aneuploidy, 28% had coexistent PSC. This led to the hypothesis that PSC was an independent risk factor for the development of colorectal neoplasia in patients with existing UC.

This hypothesis has remained a topic of extensive debate within the medical literature.15 This review aims to evaluate the available evidence to date, debate the possible mechanisms that may underlie association, and finally discuss the possible impact of any findings on current and future clinical practice.

Clinical studies
Since 1992, several studies have examined the role of PSC in the development of colorectal neoplasia in the setting of chronic UC. The investigative format of the studies evolved with time, with the early focus being on the prevalence of PSC in UC complicated by neoplasia, and later on follow up of patients with UC with or without coexistent PSC.

Of these studies, eight have concluded that the risk of colorectal neoplasia in UC is greater in patients with PSC.14 16-22 Only two studies (both from the Mayo Clinic but using different patients) have definitely concluded that there is no increased colorectal cancer risk in PSC.23 24 Two further studies do not allow definite conclusionsone because of small numbers and the other due to variable end points.25 26

Positive Studies
Following the initial paper by Broomé and colleagues,14 the association between PSC, dysplasia, aneuploidy, and colorectal cancer was re-examined in a cohort of 79 patients with extensive and chronic colitis enrolled in the Denver Dysplasia in UC study.27 This included prospective surveillance of dysplasia and ploidy status from biopsies obtained on colonoscopy. DNA aneuploidy was more common in those patients with coexistent PSC than those without. Secondly, multiple synchronous sites of aneuploidy were observed in all those with PSC and abnormal epithelial histology (dysplasia/carcinoma).

These preliminary findings reported in abstract form provide further support for the hypothesis that PSC may be an additional risk factor for colorectal cancer in chronic UC, and that the presence of aneuploidy may be a useful indicator of an increased risk of malignant transformation.

Broomé and colleagues17 then provided further evidence to support their initial hypothesis with a case control study intending to assess the absolute cumulative risk of colorectal neoplasia in patients with both UC and PSC against matched controls with UC only. A statistically significant increase in the development of neoplasia was evident in the group with coexistent PSC. A graph of their results is shown in fig 1. Patients with both UC and PSC showed a cumulative risk of developing colorectal neoplasia of 9% at 10 years, 31% at 20 years, and 50% at 25 years after diagnosis of PSC. The corresponding risks for the control group were 2%, 5%, and 10%, respectively, representing a fivefold increase in risk at 25 years. A similar risk of neoplasia in the control group to that in recent population based studies of extensive UC4 confirmed that this was a representative control group.

Figure 1 Absolute cumulative risk of developing colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis (UC+PSC) compared with patients with UC alone (p<0.001) (from Broomé and colleagues17).