Malignant transformation of the colorectal mucosa in inflammatory bowel disease

Abstract: Ulcerative colitis (UC) and Crohn's disease (CD) are disorders of unknown etiology, often referred to as inflammatory bowel diseases (IBD). The increased risk of colorectal cancer (CRC) in patients with longstanding, extensive colonic IBD is an important clinical problem. Colonoscopic surveillance, annually or every second year, with multiple biopsies for histopathological detection of dysplasia, is now used to manage this increased risk at many centers for IBD. Dysplasia is a useful prognostic marker for subsequent cancer development but has limitations including substantial inter- and intra-observer variability among pathologists. Furthermore, concomitant active inflammation makes assessment and interpretation of dysplasia difficult. There is a need for more accurate and more objective markers for neoplastic transformation of the colorectal mucosa in high-risk individuals. Although long-term treatment with 5-ASA compounds seems to lower the risk of CRC in IBD, no studies using primarily preventive drugs have been performed. The aims of this thesis were to assess the utility of other markers for malignant transformation of the colorectal mucosa and also to explore any potential chemopreventive properties of long-term oral therapy with ursodeoxycholic acid in high- risk patients with IBD. By using monoclonal antibodies, the expression of the proliferative antigens Ki-67 and PCNA was assessed in biopsy specimens with various degrees of epithelial dysplasia and inflammatory changes. Increased staining with MIB-1 and PCNA correlated with increased severity of dysplasia but also with increased inflammation. In the absence of inflammation, immunostaining with these two antibodies may complement dysplasia, especially in the indefinite changes category. Alkaline sphingomyelinase (SMase) hydrolyses sphingomyelin (SM) generating ceramide which is important in the regulation of cell growth. The activity of alkaline SMase activity is decreased in CRC and premalignant conditions and was also found to be decreased in IBDpatients. There was also an age-dependent decrease of alkaline SMase both in IBD- patients and controls. Flow cytometric DNA-analyses of biopsy specimen can detect gross chromosomal aberrations and also have the ability to correctly estimate the number of cells in proliferation (S-phase). In normal colorectal mucosa it was found that the S-phase increased linearly with age and decreased from the right colon over the transverse colon to the left colon. The fraction of G2cells increased significantly with increased S-phase fraction. No aneuploidy was detected. In 324 UC-patients undergoing colonoscopic surveillance, the S-phase of aneuploid samples was significantly increased compared to diploid, but significantly lowered in comparison with sporadic CRC. An increase in S-phase fraction in patients with IBD without active inflammation may be an additional marker for neoplastic potential in the colorectal mucosa. Ursodeoxycholic acid, a natural bile salt, has been associated with regression of experimentally induced neoplasia in rats. In a two year prospective, double blind randomized pilot study in high-risk IBD-patients, none of the ten patients in the treatment group had progression of dysplasia, while two of the nine patients in the placebo group were refered for colectomy due to progression of dysplasia. UDCA may exert chemopreventive action(s) in patients with longstanding IBD in the colon, but further studies are needed in order to determine optimal selection of patients, UDCA-dose and treatment time.