Screening and Treatment Options of Patients with Dysplasia Associated IBD

The evidence of the association of dysplasia with cancer in patients with IBD has been noticed since the first publication of Crohn and Rosenberg early in the 1900s [41-43]. The fact that dysplasia is commonly seen near areas of invasive carcinoma in up to 74% of resection specimens from IBD patients, has lead to the conclusion that this is a precursor to the invasive lesion [44]. The diagnosis of dysplasia in patients with IBD is a crucial step because in some centres it will leave the patient with either a colecto-my or life-long surveillance to prevent the development of cancer [25].

The rationale behind screening in these groups of patients is based on the recognition that CRC in these groups follows the sequence of chronic inflammation with the subsequent development of dysplasia of the colonic epithelium, progressing to carcinoma. This is roughly the same argument used in detecting and treating adenomatous polyps, since they are known to be the classical precancerous lesions in the colon and rectum. The issue when the diagnosis of dyspla-sia is established is what to do or advise next. Classically, and according to the recommendations proposed by Riddell et al., the procedure is to follow up cases with low-grade dysplasia and operate on DALMs and high-grade dysplasia. This seems at a glance to be good simple advice; however, there have been a few studies that have shown some data that has made the decision more complex. Charles Bern stein says that "when low grade dysplasia is the preoperative diagnosis, cancer may already be present in the colon in 20% of these cases". He quoted the St Marks series by saying that in about 50% of the cases of CRC in UC, low-grade dysplasia is the only type of dysplasia seen in the colonic resections adjacent or away from the tumour. It is also important to know that dysplasia may not be seen in 25% of patients with CRC complicating IBD [45]. There is also mounting evidence showing that the story of natural progression from low-grade to high-grade dysplasia and then to full-blown cancer can not always be substantiated. Dysplasia has been recognised as a pre-malignant condition since the 1980s [46]. If dysplasia is detected by random biopsy, its presence may correlate with the presence of deposits of micro-invasive adenocarcinoma. The presence of dysplasia in colonic biopsies is a reliable histological marker which can be used to predict which patients are at risk of developing CRC before there is macroscopic evidence of disease [47]. Prior to enrolling in surveillance programmes, all patients should be counselled as to the possibility of requiring a prophylactic proc-tocolectomy with either a permanent end ileostomy or formation of an ileo-anal pouch in order to prevent the future development of CRC, if the presence of dysplasia is confirmed. It is interesting to realise that most of the rarely reported cases of carcinoma arising in the ileo-anal pouch are those that have carcinoma or dysplasia in the initial resectates [18].

The British Society of Gastroenterology and the Association of Coloproctology have suggested guidelines for the screening of asymptomatic colorectal cancer in patients with inflammatory bowel disease. These guidelines suggest that colonoscopy surveillance with four random biopsies every 10 cm should commence after the patient has endured the condition for a minimum of 8 years. The risk of CRC is relatively low during the first decade of the disease. As a result, the surveillance protocols recommend three yearly colonoscopies for the first 12 years, then biannual endoscopies for the next 10 years, followed indefinitely with annual colonoscopy [48]. This is at variance with the recommendation originally suggested by Riddell et al. in their classic paper in 1983 (see Table 1) In high risk groups such as those patients with positive family histories of CRC at a young age or primary sclerosing cholangitis, annual colonoscopy is recommended [49].

The overall sensitivity of direct colonoscopy for the detection of dysplasia is between 70-85%. Biopsy of any macroscopically visible lesion is advised along with four random biopsies at 10-cm intervals. In practice, the colonoscopy may be performed more frequently, depending upon the severity of the illness and the extent of colonic involvement.

Sampling error, where the endoscopist fails to take an adequate number of biopsies to exclude dysplasia or carcinoma [50], is also a known problem. The detection of high-grade dysplasia (HGD) in flat lesions is sufficient histological evidence for the recommendation for a prophylactic colectomy to be made. Multifocal low-grade dysplasia (LGD) should also be treated with a prophylactic proctocolectomy [51, 52]. Until recently there has been no consensus as to whether the detection of a single focus of low-grade dysplasia could be managed by accelerated colonoscopic surveillance prior to the detection of HGD and the recommendation of proctocolectomy. However, analysis of prospective studies assessing continued colonoscopic screening after detection of LGD has revealed that 53% of patients with LGD developed CRC at 5 years. Twenty-four percent of patients diagnosed with LGD after colonoscopy, who had elected to be treated with proctocolectomy, had unrecognised advanced CRC after histological analysis of the colectomy specimen with a rate of progression to advanced neoplasia that approached 53% [52]. In a separate study, the presence of dysplasia was found to have a sensitivity of 81% and specificity of 79% as a marker for the presence of a synchronous CRC. The positive predictive value of the detection of LGD was 70% [53]. In view of these results and other similar studies, detection of LGD is now widely accepted as an indication for prophylactic procto-colectomy with formation of an ileo-anal pouch or end ileostomy. However, many clinicians still pursue a more conservative approach in treating LGD rather than recommending surgery, since other studies have presented a less worrisome prognosis of LGD. Befrits et al. followed 60 patients with flat LGD and found that none developed cancer on follow-up [54].

Any raised non-adenomatous mass containing evidence of dysplasia on biopsy would also require a proctocolectomy. Some suggest that dysplasia detected in adenomatous lesions can be safely treated with endoscopic resection, preventing an unnecessary colectomy. Unfortunately colonoscopy with random biopsies of macroscopically normal looking mucosa is an inherently unreliable technique due to the sporadic nature of dysplasia, which often leads to a low detection rate of positive results [55]. Inaccuracies may occur at different stages of the screening process due to inadequate colonic biopsies: macroscopically visible lesions which remain undetected after colonoscopy due to operator technique. Errors that lead to misinterpretation will lead to false positive or negative biopsy results. One of the major criticisms of CRC surveillance programmes is the failure of routine biopsy to detect the neoplasia that is subsequently found after histological analysis of colectomy specimens after surgery for symptom control, in the interval prior to the next surveillance colonoscopy. The potential for areas of dysplasia to remain undetected after colonoscopy may be a factor contributing to the failure of screening to dramatically reduce the incidence of CRC developing as a complication of IBD. This limitation of colonoscopy needs to be discussed with patients willing to enter surveillance programmes, as the limited sensitivity of this test needs to be evaluated by each individual against the potential complications that arise as a result of colonoscopy. In UK practice, the development of an iatrogenic colonic perforation or haemorrhage requiring laparoscopy occurs in approximately 1:1 000 patients undergoing colonoscopy [56]. A full discussion of all of the possible advantages of surveillance must be held with the patient prior to them enrolling in the follow-up programme, in view of the potential physical and psychological complications. The most reliable method to date for predicting the risk of CRC is the presence of confirmed dysplasia from colonoscopic biopsies. However, as yet there have been no randomised controlled trials to compare the effectiveness of different surveillance programmes in improving survival from CRC in patients with IBD. There are few actual studies which compare outcomes of surveillance against no surveillance. This is partly due to the recognition that dys-plasia is a pre-malignant condition and early detection of neoplasia with subsequent prophylactic proc-tocolectomy can reduce the number of deaths from CRC. This is a powerful argument supporting the implementation of surveillance programmes. The opposing argument focuses on the finding that surveillance has had little effect on reducing the mortality rate of IBD patients dying from CRC [57]. Histological analysis of specimens from prophylactic proc-tocolectomies performed after the detection of dys-plasia often reveals the presence of unexpected early Dukes A or B cancers. Earlier detection may result in reduced morbidity and improved survival for the individual but this may be attributable to the lead time bias of earlier diagnosis. There is no clear evidence that screening has reduced the mortality rate of patients with IBD [58].. Attention has recently been focused on developing an alternative approach to improve the efficiency of surveillance programmes. The routine practice of obtaining four random biopsies at 10-cm intervals generates a vast number of biopsies for analysis, of which only a small proportion contain evidence of dysplasia. This is an expensive and highly laborious process with a low diagnostic yield for both the endoscopist and pathologist. There is great interest in developing new techniques which can target areas of macroscopically invisible dysplasia directly and obviate the need for random biopsies. Chromoendoscopy is the term given to the technique of endoscopically spraying the colonic mucosa with dyes such as 0.1% methylene blue or

0.4. indigo carmine to emphasise unusual mucosal irregularities [59]. This is an easily adapted procedure which can be performed by the application of dye to the colonic mucosa from a conventional colonoscope. The rational behind chromoendoscopy is based on the dyes not being absorbed by the mucosa but simply pooling in the mucosal pits allowing easier endoscopic identification of abnormal mucosa [60]. In Vivo studies in animal subjects have allowed analysis of patterns of dye uptake in colonic mucosa which has been repeatedly verified by histo-logical analysis of the resected or biopsied specimens [61]. Clinical studies utilising chromoendoscopy have indicated that this improved endoscopic technique provides better improved detection rates of dysplastic lesions. The detection of flat lesions by routine colonoscopy is very difficult as the mucosal changes are very subtle. Intravital staining significantly improves the endoscopic detection of flat lesions [62]. These lesions are classified according to the pit pattern system which was developed in response to the enhanced images obtained from using magnifying endoscopes. Two separate prospective trials comparing the detection rates of neoplastic lesions by traditional random biopsy on routine colonoscopy followed by immediate repeat colonoscopy and targeted biopsy after mucosal staining both testify that detection of dysplasia is significantly improved by chromoendoscopy [63, 64]. This finding has significant implications for the screening of patients with IBD, as the improved detection rates will result in more patients undergoing prophylactic proctocolec-tomies at an earlier stage, which may inevitably include the detection of synchronous CRC at earlier stages. Pan-colonic chromoendoscopy also detects a large number of non-neoplastic lesions. To maximise the detection of dysplasia and minimise the biopsy of non-neoplastic tissue, the endoscopist must adhere to targeting biopsies of lesions with suspicious staining patterns as determined by the pit pattern system— grade III and IV lesions are likely to represent neo-plastic change. In a recent article on chromoen-doscopy, it was suggested that the so-called SURFACE guidelines in ulcerative colitis be followed [65].

1. Strict patient selection. Patients with histological-ly proven ulcerative colitis and at least an 8-year duration in clinical remission. Avoid patients with active disease.

2. Unmask the mucosal surface. Excellent bowel preparation is needed. Remove mucus and remaining fluid in the colon when necessary.

3. Reduce peristaltic waves. When drawing back the endoscope, a spasmolytic agent should be used (if necessary).

4. Full length staining of the colon. Perform full length staining of the colon (panchromoendoscopy) in ulcerative colitis rather than local staining.

5. Augmented detection with dyes. Intravital staining with 0.4% indigo carmine or 0.1% methylene blue should be used to unmask flat lesions more frequently than with conventional colonoscopy.

6. Crypt architecture analysis. All lesions should be analysed according to the pit pattern classification. Whereas pit pattern types I-II suggests the presence of non-malignant lesions, staining patterns III-V suggest the presence of intraepithelial neoplasias and carcinomas.

7. Endoscopic targeted biopsies. Perform targeted biopsies of all mucosal alterations, particularly of circumscript lesions with staining patterns indicative of intraepithelial neoplasias and carcinomas (pit patterns III-V).

The use of high resolution endoscopy and dye staining is 97% sensitive and 93% specific in predicting neoplasia [66]. Novel techniques that have been developed include ultra high-powered magnifying endoscopes which have 1 000 times greater magnification and are able to visualise cellular microstructures. The resultant images of In Vivo cells have such clarity that the possibility exists in the future of endo-scopically generated virtual histology [69].

Other experimental techniques include Raman spectroscopy, fluorescence spectroscopy light scattering spectroscopy, optical coherence tomography and confocal laser microscopy. However, at this time, these techniques are still experimental [68]. It is possible that in the future these diagnostic techniques will be used with molecular markers to improve detection of neoplasia. The benefit of surveillance techniques utilising chromoendoscopy for the detection of dysplasia in patients with long-term IBD are enormous and as such are likely to initiate a radical change in current practice during this decade. There is wide support for offering patients with adenomalike polypoid dysplasia a local resection if certain criteria are met. These include the absence of flat dysplasia in the multiple biopsies of the area adjacent to the lesion or the absence of flat or raised dysplasia in other parts of the colon, and the willingness of the patient to undergo continued surveillance [13]. Laser fluorescence spectroscopy for In Situ dysplasia diagnosis and faecal DNA testing are some of the techniques that have been indicated as being useful in the future [69]. A recent study had suggested that in longstanding extensive ulcerative colitis, the severity of colonic inflammation is an important determinant of the risk of colorectal neoplasia. Endoscopic and histological grading of inflammation could allow better risk stratification for surveillance programmes [70].

As we mentioned before, there seems to be no standard or universally agreed treatment for dysplasia. It was Blackstone et al. who advocated in a case study the importance of having a definitive radical surgery (total colectomy) in cases of dysplasia and demonstrated the horrid prognosis relating to the raised dys-plastic lesions in patients with IBD [71]. Adenomalike lesions that occur proximal to histological areas of colitis (i.e. right-sided lesion in a patient with left-sided UC), can easily be diagnosed as a sporadic adenoma because it is well known that dysplasia related to IBD develops only in areas involved by the inflammatory process. However, adenoma-like lesions that occur within areas affected by colitis are more difficult to distinguish from true polypoid dysplastic lesions related to the underlying colitis [24, 34]. Recent data, primarily based on the results of two follow-up studies, suggest that IBD patients with an adenoma-like DALM, regardless of whether it has been determined as representing a sporadic or an IBD-related lesion, may be treated adequately by polypec-tomy and continued surveillance if there is no evidence of flat dysplasia elsewhere in the patient or especially the base of the polyp [72-74]. Further studies may be needed to verify the above observations but for the time being it seems that this has momentarily alleviated the pressure on the pathologists to differentiate between DALM and sporadic adenoma.

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