Cancer Prophylaxis

Colorectal carcinoma is the most serious long-term complication of chronic ulcerative colitis. The relation between long-standing ulcerative colitis and cancer is well documented although the risk of malignancy was overestimated in the past. It is believed that cancer develops through a sequence of

Fig. 4. Operative specimen of ulcerative colitis with pseudopolyposis

changes from no dysplasia to low-grade and highgrade dysplasia and finally adenocarcinoma. The endoscopic appearance of adenocarcinoma of the cecum in a patient with ulcerative colitis is presented in Figure 5.

The overall absolute risk of colorectal cancer in longstanding extensive or total ulcerative colitis is estimated to be 10-15%, which is 6-10 times higher than expected in the general population. The risk of malignant transformation is not high (0.3-1.0%), but does remain a constant threat especially after a 10-year duration of the disease, when the disease involves the entire colon and when colitis had its onset in childhood [39]. In a meta-analysis by Eaden [40], the cumulative risk of developing colorectal cancer was 8% at 20 years after the diagnosis, rising up to 18% at 30 years. In patients aged 15-39 years at onset of extensive disease, the cumulative risk of developing carcinoma after 25 years is 12% [41]. The cumulative cancer risk in patients with left-sided colitis at the time of diagnosis is less than 5% after 30 years. In recent meta-analysis, the estimated col-orectal cancer risk in all patients with ulcerative colitis is 2% at 10 years, 8% at 20 years and 18% at 30 years, irrespective of the extent of the disease [40]. However, treatment of carcinoma or cancer prophylaxis is an indication for operation in 15-30% of patients who undergo elective colectomy. The risk of developing cancer is influenced by the extent and duration of disease while the age of onset of colitis as an independent factor for developing carcinoma remains controversial. Patients with extensive dis ease (proximal to the splenic flexure) of long duration (>8 years) have a major risk of developing colorectal carcinoma. The severity of the colitis does not correlate with the cancer risk. When cancer occurs, it is usually multicentric and poorly differentiated. Since it is generally believed that cancer in ulcerative colitis develops through a sequence of changes from dysplasia to carcinoma, the presence of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) should be considered to be the particular points of the disease where preventative measures should be instituted. There are several areas of misunderstanding regarding this issue. First, the term dysplasia is a complicated concept and is not always accepted the same way. Second, there are technical hitches regarding the detection of dysplasia, problems with histopathological assessment of biopsy specimens and lastly there is considerable debate about what kind of preventive measures should be initiated-colonoscopic surveillance or total colectomy. By definition, dysplasia is an unequivocal neoplastic change confined to the epithelium [42]. Dysplasia may be patchy and unevenly distributed throughout the colon demanding many biopsies to reduce the risk of sampling errors. It has been estimated that approximately 33 biopsies are necessary to allow 90% confidence in the detection of dysplasia. In practice, biopsies taken from six to ten different sites throughout the colon and rectum have proved to be safe in detecting dysplasia and have a low risk of missing incurable carcinoma [43, 44]. The difficulty with histopathological assessment is in inter- and intraob-server variations in dysplasia assessment. Agreement in the evaluation of dysplasia among experienced pathologists has only reached 42-65% [45, 46]. Therefore, grading of dysplasia should always be evaluated by two experienced pathologists. Apart from controversies in evaluation of dysplasia in ulcerative colitis, there are more controversies concerning treatment. Some studies have suggested that LGD has a low risk of progression to HGD or col-orectal carcinoma and have advocated a conservative approach with an increased surveillance schedule [47, 48]. Studies have shown that if LGD does progress to advanced lesions, it does so within 3 years. Therefore, intensive surveillance with repeated colonoscopies every 6 months with four quadrant biopsies every 10 cm should be recommended and colectomy should be performed only for those developing HGD or dysplasia associated lesion or mass (DALM). Others have estimated the risk of progression of LGD to more advanced lesions and colorectal carcinoma to be high enough and recommend prophylactic colectomy [49, 50, 51]. In some cases, flat LGD can progress to colorectal carcinoma without going through a stage of HGD [52]. This fact supports

prophylactic colectomy in cases of flat LGD. LGD in the presence of DALM is a sensitive predictor of simultaneous colorectal cancer or progression to col-orectal cancer and with the current available evidence, the presence of DALM should be an indication for colectomy. Cancer prophylaxis with the required diagnostic procedures and management are presented in Figure 6.

If LGD is found at a single location, increased vigilance regarding surveillance is advocated along with annual colonoscopy. In cases of multifocal LGD, a new examination should be performed in 6 months and if multifocal LGD is present, the patient should be advised to undergo proctocolectomy. There are wide variations in the management of LGD in ulcerative colitis compared with HGD and DALM where there seems to be more uniform agreement. Findings of dysplasia associated lesion or mass (DALM) with HGD or HGD in flat mucosa are considered as indications for surgery [53, 54]. Pedunculated adenomas in dysplasia-free mucosa should be managed with snare polypectomy as in non-colitis patients. Findings of sessile polyps should be regarded as a potential DALM and prophylactic colectomy should be discussed.

There are a lot of controversies and different and opposite opinions regarding treatment of ulcerative colitis that may lead to some confusion for the one who has to deal with this disease. A lot of knowledge

Fig. 6. Cancer prophylaxis has been accumulated during the past few decades, altering our view and understanding of ulcerative colitis with inevitable repercussion on treatment modalities. There is a growing tendency of conservative treatment in ulcerative colitis using new medications in order to defer or abandon surgery as much as possible. However, surgery should be considered as complementary and not competitive to medical treatment, and not as a last resort because it is a very effective treatment. An experienced gastroenterologist and surgeon, assisted by the radiologist and pathologist, should act as a team in decisions regarding the optimal treatment plan for the patient. Treatment priorities must focus less on saving colons than on saving lives.

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