Identification of dysplasia in inflammatory bowel disease represents a major challenge for both clinicians and pathologists. Clear diagnosis of dysplasia in inflammatory bowel disease is sometimes not possible with biopsies remaining "indefinite for dysplasia." Recent studies have identified molecular alterations in colitis-associated cancers, including increased protein levels of alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2. In order to analyze the potential diagnostic use of these parameters in biopsies from inflammatory bowel disease, a tissue microarray was manufactured from colons of 54 patients with inflammatory bowel disease composed of 622 samples with normal mucosa, 78 samples with inflammatory activity, 6 samples with low-grade dysplasia, 12 samples with high-grade dysplasia, and 66 samples with carcinoma. In addition, 69 colonoscopic biopsies from 36 patients with inflammatory bowel disease (28 low-grade dysplasia, 8 high-grade dysplasia, and 33 indefinite for dysplasia) were included in this study. Immunohistochemistry for alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2 was performed on both tissue microarray and biopsies. p53 and alpha-methylacyl coenzyme A racemase showed the most discriminating results, being positive in most cancers (77.3% and 80.3%) and dysplasias (94.4% and 94.4%) but only rarely in nonneoplastic epithelium (1.6% and 9.4%; P < .001). Through combining the best discriminators, p53 and alpha-methylacyl coenzyme A racemase, a stronger distinction between neoplastic tissues was possible. Of all neoplastic lesions, 75.8% showed a coexpression of alpha-methylacyl coenzyme A racemase and p53, whereas this was found in only 4 of 700 nonneoplastic samples (0.6%). alpha-methylacyl coenzyme A racemase/p53 coexpression was also found in 10 of 33 indefinite for dysplasia biopsies (30.3 %), suggesting a possible neoplastic transformation in these cases. Progression to dysplasia or carcinoma was observed in 3 of 10 p53/alpha-methylacyl coenzyme A racemase-positive, indefinite-for-dysplasia cases, including 1 of 7 cases without and 2 of 3 cases with p53 mutation. It is concluded that combined alpha-methylacyl coenzyme A racemase/p53 analysis may represent a helpful tool to confirm dysplasia in inflammatory bowel disease.
[Show abstract][Hide abstract] ABSTRACT: The risk of developing colorectal cancer in patients with colitis-associated dysplasia is considerable. Surveillance programs in patients with ulcerative colitis and Crohn's disease aim to detect dysplastic lesions early and rely heavily on taking random biopsy samples along the length of the colon. Diagnosing dysplasia can be difficult because of the heterogeneous endoscopic appearance of dysplasia and the poor interobserver agreement among pathologists when grading dysplasia. Colitis-associated dysplasia may present as a dysplasia-associated lesion or mass (DALM), which may be indistinguishable from a sporadic adenoma in non-colitic tissue, or may arise in flat mucosa of endoscopically normal appearance. Information about the endoscopic appearance, the colonic distribution and the histopathological grade of colitis-associated dysplasia is required to define the optimal treatment. This Review summarizes the endoscopic and histopathological features of colitis-associated dysplasia and the requirements for optimal interaction between endoscopists and pathologists, with the aim of reducing the uncertainties in the diagnosis of dysplastic lesions and improving the management of colitis-associated dysplasia.
[Show abstract][Hide abstract] ABSTRACT: Chronic ulcerative colitis (UC) is associated with an increased colorectal cancer risk which may be secondary to repetitive mucosal injury. Both epigenetic methylation and the classic adenoma-to-carcinoma sequence have been implicated in this malignant transformation, but the underlying molecular mechanisms remain poorly defined. This study compares the molecular characteristics of colitis-associated and common colorectal cancers.
Nineteen patients with colorectal adenocarcinomas arising within UC were matched for age and cancer site with 54 patients with sporadic adenocarcinomas. Tumor tissue was examined for BRAF mutations, CpG island methylator phenotype (CIMP), and MLH1 promoter methylation. Mutations of KRAS and p53 were assessed by sequencing.
Patient demographics were similar for the two groups. CIMP was observed in 22% of sporadic colorectal cancers and in 5% of UC cancers (P = 0.162). Rates of BRAF mutation (4% vs 5%, P = 1.0), MLH1 methylation (9% versus 5%, P = 0.682), and KRAS mutations (24% versus 32%, P = 0.552) were similar between the groups. However, colitis-associated colorectal cancers were more likely to have a p53 mutation compared to sporadic adenocarcinomas (95% versus 53%, P = 0.001). The dominant mutation for colitis-associated cancers was a mutation in codon 4, representing half of the mutations. Furthermore, colitis-associated cancers had a higher rate of mutation in codon 8 (48% versus 6%, P < 0.001) than sporadic counterparts.
Unlike other inflammatory gastrointestinal cancers, colitis-associated colorectal cancers do not preferentially arise via a methylator pathway when compared to sporadic colorectal cancers. Chromosomal instability remains an important etiology, but with a unique p53 frequency and mutation pattern.
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