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Fig. 6.30 Adenomas with high-grade dysplasia. A Loss of normal glandular architecture, hyperchromatic cells with multi-layered irregular nuclei and loss of mucin, high nuclear/cytoplasmic ratio. B Marked nuclear atypia with prominent nucleoli. C Adenoma with focal cribriform pattern .

Fig. 6.31 Serrated adenoma with irregular indentation of the neoplastic epithelium.

Ulcerative colitis (UC)

Development of carcinoma Is apparently metachronous to the development of Intraepithelial neoplasia (classified as low-grade and high-grade) complicating chronic colitis. Because invasion can be associated with intraepithelial neoplasia exhibiting relatively mild morphological changes, high-grade intraepithelial neoplasia is diagnosed in colitis on the basis of abnormalities that are less severe than the criteria for high-grade intraepithelial neoplasia in adenomas. It may be flat or present as a 'dysplasia associated lesion or mass' (DALM); the latter is often associated with a synchronous carcinoma arising beneath the dysplastic surface. DALMs are considered high-grade lesions through their architecture alone, and both DALM of any grade of dyspla-

Fig. 6.32 Microtubular adenoma.
Fig. 6.33 Apoptotic cells in an adenoma demonstrated by M30 immunohistochemistry.

sia and high-grade flat dysplasia are associated with invasive carcinoma in about 40% of cases. The diagnosis of DALM and high-grade flat dysplasia usually leads to total colectomy {1687}. It may be difficult to distinguish a DALM from an incidental adenoma in a patient with UC.

Attempts have been made to identify early dysplastic lesions in UC with cell cycle proliferation markers. Topoiso-merase II alpha and Ki-67 have been shown to increase significantly over baseline expression in UC related dys-plasias. Ki-67 positive cells are found both at the surface and the base of the crypts, indicating a fundamental deregulation of the proliferative cell pool {1368}. Mutations of TP53 appear to be an early event and are already present in intraepithelial neoplasia associated with UC, in contrast to the adenoma-carcinoma sequence in sporadic colorectal carcinomas. Some TP53 mutations have even been observed in non-dysplastic mucosa of chronic inflammation {516, 1463, 2175}.

Alterations of p16 have also been identified in early UC but only very infrequently in adenomas. Both tumour tissue and multiple colorectal cancer cell lines studied showed absence of LOH in 9p 1 {2019, 878}.

Microsatellite instability and gene alterations in p16 and p53 may represent early events during the development of dysplasia and carcinoma, and these changes may lead to susceptibility for allelic loss of other genes such as APC and DCC. It has been shown that LOH of genetic areas close to the VHL locus on 3p is frequently present in DALM lesions and, less frequently, in flat dysplastic lesions. These changes are not usually seen in sporadic adenomas {515}. This may indicate that dysplasia in UC and sporadic adenomas may follow different genetic pathways.

Crohn disease

Intraepithelial neoplasia, classified as low-grade or high-grade, is associated with a high proportion of Crohn carcinomas, either adjacent to the invasive lesion or at a distance from it {1757}. Similar to UC, polypoid dysplastic lesions are diagnosed as DALM in Crohn's disease.

Mucinous adenocarcinomas are seen in Crohn disease more frequently than in

Mucin Stalk
Fig. 6.34 Tubulovillous adenoma with pseudoinvasion. Small clusters of adenomatous cells produce multilocular, large mucin deposits that expand the adenoma's stalk. This growth pattern resembles mucinous carcinoma but is not malignant.

sporadic colorectal carcinomas {656}. There is an increased frequency of ade-nocarcinomas within perianal fistulas, and of squamous cell carcinomas of the anal mucosa {992}.

Similar to UC, TP53 and c-KRAS mutations are observed earlier in Crohn-asso-ciated intraepithelial neoplasia than in the adenoma-carcinoma sequence of sporadic colorectal cancer {1562}.

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