Pathogenesis of CRC in IBD

The pathogenesis of CRC in IBD is poorly understood. However, several lines of evidence suggest that the pathobiology is different than sporadic CRC:

1. the mean age of developing CRC in the setting of IBD is lower than sporadic CRC (40-50 vs. 60 years).

2. Dysplasia in UC is preceded by a long history of chronic inflammation and can be found at distant sites from the cancer. In contrast, dysplasia in sporadic CRC is usually associated with a discrete polyp without inflammation.

3. Mutations in the ras protooncogene are present in 40-60% of sporadic CRC and are probably an early event; in contrast, these mutations are less frequently observed in cancer associated with UC, and are probably a late event [26-27].

4. Loss of heterozygosity for the p53 gene and src activation occur earlier in cancers associated with IBD than in sporadic CRC. Src activity in UC correlates with the degree of dysplasia [28].

5. Abnormalities of the p53 locus are absent in non-dysplastic mucosa of patients with sporadic CRC. In contrast, non-dysplastic mucosa in UC frequently has aneuploid DNA content and may show clones of cells with loss of heterozygosity of the p53 gene [29].

It is generally accepted that CRC in IBD is preceded by dysplasia, which is defined as unequivocal neo-plastic epithelium and is currently the most important and best-defined marker of an increased risk of malignancy. Dysplasia is present in >70% of UC

patients with carcinoma. Although it may occur in any portion of the colon, it typically parallels the location of cancer arising from chronically inflamed mucosa [30-32]. From an endoscopic viewpoint, dys-plasia is characterised as flat (endoscopically invisible but detected in mucosal specimens) or raised (endoscopically visible), in which case "dysplasia associated lesions or mass" (DALM) is applied, a term that was coined by Blackstone et al. in 1981 [33]. In their study, 12 of 112 patients with long-standing UC were found to have a DALM, and of these, seven (58%) had carcinoma. Given the strong association with cancer, the presence of DALM constituted a strong indication for colectomy, which has become the standard therapy for this type of lesion. DALM are a heterogeneous population of tumours that may endoscopically appear as a plaque, mass (irregular, broad-based or strictured lesions), a discrete sessile nodule, or polyp. The cancer risk is not equal among these various subtypes. Unfortunately, most of the previous studies of UC associated DALMs failed to evaluate these lesions in relation to their gross appearance. For instance, there is one specific subtype of discrete DALM that endoscopically and histo-logically resembles a sporadic adenoma (isolated dysplastic nodule or polyp) and, as such, poses a difficult diagnostic challenge both to clinicians and to pathologists [34]. This is a critically important distinction, because an adenoma-like DALM is a tumour that arises as a result of UC and, thus, is an indication for colectomy, whereas an adenoma which is also by definition a "polypoid dysplastic lesion", the development of which is unrelated to the underlying chronic colitis (but coincidentally exists with it), is usually treated by polypectomy.

Since both UC and sporadic adenomas (SA) are not uncommon disorders, it is not surprising that gastroenterologists regularly encounter patients who have both conditions. Sporadic adenomas coexist with UC if they are located next (proximal) to the colitis because UC-related dysplasia does not develop from non-inflamed epithelium. UC associated adenoma-like DALMs were classified as lesions that were located within histologically proven areas of colitis and were associated with either synchronous or metachronous flat dysplasia or adenocarcinoma [35].

A number of clinical, histologic and molecular features have been studied to help make a distinction between DALM and SA:

1. patients with non-adenoma-like DALM are more likely to be younger and have a longer duration of disease, more extensive disease, and larger lesions [36].

2. Lesions that appear endoscopically as adenomas (pedunculated or sessile) rather than having other characteristics (such as flat, ulcerated, or plaque like appearance), even if found within an area of histologic colitis, may have a favourable prognosis with endoscopic removal and close follow-up [35, 37, 38].

In addition to the clinical and histologic features described above, several molecular markers have been proposed for distinguishing DALM from SA. Two of these are beta catenin and p53 [39-40]. Beta catenin is a cell membrane protein that accumulates more frequently in the nuclei of cells within sporadic colon cancer as compared to DALM. Mutations with p53 (a tumour suppressor gene) occur more frequently in DALM than sporadic adenomas. Several studies have provided evidence that p53 polymorphism at codon 72 (Arg and Pro alleles) may be associated with a high risk of malignancies. A recent study investigated Arg72Pro polymorphism in UC and found that p53 Pro homozygosis was more frequent in patients who had a continuous disease and, therefore, may also favour the progression from dysplasia to colon cancer [41].

The predictive value of dysplasia has been studied in UC. Although dysplasia is a marker for future or concurrent malignancy, it can also regress or remain stable for long periods. Most patients with dysplasia do not have cancer and dysplasia is absent in the colonic regions distant from the malignancy in 25-30% of patients [42-43].

The association between dysplasia and CRC in CD appears to be similar to that in UC. Dysplasia is present in 83% of patients diagnosed with CRC, and dys-plasia distant from the cancer is found in 23-70%. In contrast, dysplasia is much less common in colecto-my specimens of patients with CD than without CRC, and has occurred in only 2% of the specimens in one series [44-45].

Interpretation of biopsy samples may be confounded by interobserver variation in the recognition and grading of dysplasia. A uniform terminology for dysplasia in IBD has been proposed [29]. The classification categories histology as:

1. negative.

2. Indefinite (with subgroups of probably negative, unknown, and probably positive.

3. Positive (with subgroups of low grade and highgrade dysplasia).

Dysplasia may be difficult to distinguish from inflammation and regeneration on histologic sections. As a result, the presence of dysplasia should be confirmed by an experienced pathologist. The criteria for dysplasia stress the uniform clonal nature of dysplastic changes, which affects equally all parts of the crypt and surface epithelium. In contrast, regenerative changes are usually most prominent at the base of the crypts and show evidence of maturation as they migrate toward the crypt surface.

Other architectural and cytological abnormalities seen in regards to dysplastic epithelium include [29]: increased epithelium proliferation and mitoses; increased epithelial height; branching of crypts; back-to-back glandular formation; variation in the size and shape of nuclei; increased nuclear/cytoplas-matic ratio; altered nuclear polarity globet cells.

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