Genetics of Dysplasia

Although several other studies have evaluated immunohistochemical findings in these two groups of lesions (DALM vs. sporadic adenoma), none have been shown to be useful in this differential diagnosis

Table 4. Immunohistochemistry in DALM vs. sporadic adenoma

DALM

Sporadic adenoma

P53

+

-

Bcl-2

-

+

B-catenin

-

+

[25,26]. However, some investigators have suggested that IBD-associated adenoma-like DALMs has a higher degree of p53, and a lower degree of nuclear beta-catenin and bcl-2 staining in contrast to sporadic adenomas, thus p53 protein expression favours DALM, and expression of bcl-2 and nuclear B-catenin favours a sporadic adenoma (Table 4) [27, 28].

One study of UC-associated dysplasia and carcinoma has shown that the tumour-suppressor gene APC is demonstrated infrequently and plays an unimportant role compared to sporadic colorectal cancers. It has been shown that the APC gene was mutated in more than 60% of sporadic adenomas and CRC [29], while it was mutated in approximately 6% of colitic cancers [30].

Mutation in K-ras has been reported in cases of ulcerative colitis with a villous and hypermucinous mucosal surface prior to the appearance of dysplasia and it was suggested that these particular cases should be followed-up more frequently as a potential risk lesion for cancer development [31]. However, the majority of the studies revealed a lower incidence of K-ras mutation in UC-associated cancer compared to sporadic ones [32]. In a study by Odze et al.,there were no significant differences in the frequencies of loss of heterozygosity (LOH) of 3p, APC or p16 in the UC-associated adenoma-like lesions that occurred within areas of colitis compared to those that occurred in a background of normal mucosa. These data suggest that UC-associated flat dysplastic (non-adenoma-like) DALMs have a different molecular genotype than UC-associated adenoma-like lesions as well as non-UC sporadic adenomas, although the latter two lesions are pathogenetically similar, if not identical, to one another [33, 34]. The tumour-suppressor gene p53 is shown by many investigators to be altered in UC-associated dysplasia and carcinoma. Some use it to differentiate between reactive inflammatory epithelial changes and true dysplasia and others use it as a tool to discriminate between DALM and sporadic adenoma. Its positivity favours dyspla-sia over reactive change and DALM over a sporadic adenoma [35, 29].

Some authors reported clonal chromosomal alterations in 85% of colitic cancers, 86% of UC-associat-

ed dysplasia and 36% of non-neoplastic epithelium [36]. The high rate of chromosomal alterations in non-neoplastic epithelium in colitic cancer, compared to the very low rate in sporadic cancers, has lead to the suggestion that these changes appear early in the neoplastic pathway of colitis.

Microsatellite instability was reported in cases of high-grade dysplasia associated with IBD and also in cases of colorectal cancer in a range between 46 to 50% in some studies and 3% in others. [37, 38]. Mutation of the p16INK4a promoter region (an inhibitor of the cyclin-dependent protein kinase 4 and 6) was not demonstrated in cases of sporadic colonic cancers. However, it has been shown to be present in 70% of dysplastic lesion and 100% of colitic cancers in IBD patients [39]. Expression of apop-tosis-related proteins like Fas and Bcl-xl (both with negative or weak expression in sporadic tumours and positive in UC-associated neoplasia) is sometimes useful in distinguishing between IBD-dysplasia and sporadic adenoma, thus leaving the patient with local resection rather than colectomy [40].

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