Incidence of Cancer and Screening in Inflammatory Bowel Disease


• All patients, regardless of extent of disease at initial diagnosis, should undergo a screening colonoscopy a maximum of 8 years after onset of symptoms, with multiple biopsy obtained throughout the entire colon, to assess the microscopic extent if inflammation

• Patients with ulcerative proctitis or ulcerative proctosigmoiditis are not considered at increased risk for IBD-related CRC and thus may be managed on the basis of average risk recommendations

• Patients with extensive left-sided colitis should begin surveillance with 1–2 years after the initial screening endoscopy

• After two negative exams (no dysplasia or cancer), further surveillance exams should be performed every 1–3 years

• Patients with PSC should begin surveillance colonoscopy at the time of PSC diagnosis and then yearly

• Patients with a history of CRC in a first-degree relative, ongoing active endoscopic or histologic inflammation, or anatomic abnormalities (shortened colon, multiple pseudopolyps, or stricture), may from more frequent surveillance colonoscopy

• Representative biopsy specimens from each anatomic section of the colon is recommended. Though no prospective trails have determined the optimal number of biopsies to take, one study has recommended a minimum of 33 biopsy specimens

• Surveillance colonoscopy should ideally be performed when patient is in remission

• These recommendations apply to Crohn’s colitis who have disease involving at least one-third of their colon


Reprinted from Gastroenterology; 138(2). Farraye FA, Odze RD, Eaden J, Itzkowita SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. p. 746–74.e4. ©2010 with permission from Elsevier




Table 60.2
Recommendations from the British Society of Gastroenterology

A210762_2_En_60_Tab2_HTML.gif


Reproduced from Gut. Cairns SR, Scholefield JH, Steele RJ, et al. 59:666–89. ©2010 with permission from BMJ Publishing from BMJ Publishing Group Ltd


Several factors influence the success of surveillance. Firstly, the ability to detect dysplasia may be variable. Random biopsy sampling was based on the presumption that dysplasia is frequently not associated with visible mucosal abnormalities. To detect dysplasia with 90 % probability, 33 serial colonic biopsies from four quadrant biopsy specimens need to be obtained every 10 cm from each anatomical segment of the colon [67]. This practice has been endorsed by multiple societies [24]. Although possibly true at the inception of surveillance, evolution in endoscopic technology over the years, through standard definition colonoscopy using video chips to high-definition colonoscopy and indeed evidence that most dysplasia is visible at standard white light colonoscopy has challenged this view [17, 68]. Furthermore, random biopsies sample well less than 1 % of total colonic mucosa and one study suggested that up to 1266 random biopsies would be needed to detect one additional episode of dysplasia [69, 70]. In a study in which UC patients underwent colonoscopy every 2 years, interval cancers were observed to develop between 10 and 28 months after dysplasia-free examination [71]. Dysplasia can still be present in a normal appearing colon [17]. Additional aspects such as resectability of dysplasia, anatomical features such as pseudopolyps and a shortened tubular colon may pose difficulties with dysplasia detection. Colonic inflammation can also make pathologic discrimination of dysplasia difficult, thus surveillance should ideally take place when the patient is in clinical remission. All this should be discussed carefully with patients when committing to a surveillance program. Despite this, evidence suggests that patients do not wish to consider colectomy until there is a relatively high certainty of cancer underpinning the importance of careful considerations and meticulous assessment using the best available technology and skill to detect and reset dysplasia to avoid IBD-CRN and colectomy [72].

Meanwhile, new imaging techniques such as chromoendoscopy , narrow band imaging, and confocal endomicroscopy have been developed as an adjunctive technique to detect more subtle mucosal abnormalities. Multiple studies have demonstrated a superior diagnostic yield and therapeutic advantage with chromoendoscopy when compared with standard random biopsy and white light technique for index screening of dysplasia in colitis [7378]. Meta-analysis of these trials supports the use of chromoendoscopy with targeted biopsies for detecting dysplasia being 8.9 times more likely to detect any dysplasia and 5.2 times more likely to detect non-polypoid dysplasia than white light endoscopy with random biopsy [79, 80]. Such evolution in knowledge has seen cautious translation in societal recommendations over the years. Thus, the ACG 2010 guidelines considered it premature to endorse chromoendoscopy in low-risk patients [4]. The CCFA 2004 and AGA 2010 guidelines, however consider chromoendoscopy with targeted biopsies as a reasonable alternative to white light endoscopy for endoscopists experienced in this technique [2, 3]. All recent European guidelines (ECCO, BSG, NICE) and recent ASGE guidance endorse chromoendoscopy with targeted biopsies as a surveillance protocol of choice [58]. The recently published SCENIC international consensus statements recommend chromoendoscopy over standard white light colonoscopy and suggest chromoendoscopy over high-definition colonoscopy for dysplasia surveillance in IBD [68]. Meta-analysis showed a significantly greater proportion of dysplasia detection at chromoendoscopy (RR 1.8, absolute risk increase 6 %) then white light colonoscopy alone [68]. This strategy has also been shown to be cost-effective especially with increasing surveillance interval based on the risk of CRC [81]. Although the SCENIC consensus recommends chromoendoscopy over high-definition white light colonoscopy it was acknowledged that this recommendation is conditional being based on a small observational study [68, 82]. Where chromoendoscopy expertise is not available SCENIC recommends high-definition over standard white light colonoscopy [68]. Chromoendoscopy involves the use of topical contrast agents, either 0.1 % methylene blue or 0.03–0.5 % indigo carmine. Excellent bowel preparation is a prerequisite. Colonic mucosa is segmentally sprayed with contrast agent after cecal intubation and upon withdrawal, using a spray catheter or through the forward water–jet channel using an automated pump [7375, 80, 81, 83]. Chromoendoscopy enhances mucosal irregularities and helps to delineate the lesion morphology, size, and border to evaluate for endoscopic features of submucosal invasion. Thus, endoscopically resectable lesions may be resected if feasible or tattooed and referred to an endoscopist with expertise in endoscopic mucosal resection or dissection as appropriate. Targeted biopsies should be taken from lesions deemed unresectable endoscopically and lesions of uncertain significance. Furthermore, at least two histological staging biopsies from each colonic segment are recommended to determine histological extent and severity of disease, which in turn affects the risk of dysplasia [5, 6, 8, 9]. Random biopsies however, are not recommended if chromoendoscopy is used for dysplasia surveillance [1, 5, 6, 8, 48]. Successful delivery of dysplasia surveillance using chromoendoscopy hinges on several factors. These include appropriate training (endoscopist and nurses), lesion recognition and its associated learning curve, inter-observer variability amongst pathologists in identifying and grading dysplasia and indeed operational barriers such as availability of dye and equipment, procedural time resulting in some hesitancy amongst gastroenterologists in adopting this modality and in some instances referral to “experts” to provide this [68]. Furthermore, heightened sensitivity of chromoendoscopy in detecting dysplastic foci notwithstanding, the natural history of additional, smaller, flatter lesions identified at chromoendoscopy is poorly understood [84]. The rate of progression from indefinite and low-grade dysplasia to cancer appears to be low some in high-risk cohorts even when variables such as primary sclerosing cholangitis and previous advanced dysplasia are factored in [3033]. To add to this conundrum, data from the Surveillance, Epidemiology and End results Medicare-linked database of patients over 67 years showed that interval cancers 6–36 months after colonoscopy occurred in much higher proportion of patients with IBD (15.1 % with Crohn’s disease and 15.8 % with ulcerative colitis) than patients without IBD (5.8 %) suggesting that clinically relevant areas of neoplasia may be missed with current colonoscopy surveillance [85]. However, the futility of random biopsy has been demonstrated repeatedly in prospective studies. Meanwhile, the evolution in our knowledge of the natural history of dysplasia and the clinical implications of dysplasia found by chromoendoscopy through its wider adoption may close many gaps in our understanding of its true utility. The bulk of evidence favors chromoendoscopy for surveillance and is backed by several scientific societies and international consensus opinion [5, 6, 8, 9, 68]. Several organizations elected not to endorse the SCENIC recommendations feeling that additional studies are needed to confirm that clinical outcomes are improved with chromoendoscopy. A summary of recommendations from the SCENIC consensus for surveillance and management of dysplasia in patients with IBD is outlined in Table 60.3.


Table 60.3
Summary of recommendations for surveillance and management of dysplasia in patients with inflammatory bowel disease






































 
Detection of dysplasia on surveillance colonoscopy

1.

When performing surveillance with white-light colonoscopy, high definition is recommended rather than standard definition (strong recommendation, low-quality evidence)

2.

When performing surveillance with standard-definition colonoscopy, chromoendoscopy is recommended rather than white-light colonoscopy (strong recommendation, moderate-quality evidence)

3.

When performing surveillance with high-definition colonoscopy, chromoendoscopy is suggested rather than white-light colonoscopy (conditional recommendation, low-quality evidence)

4.

When performing surveillance with standard-definition colonoscopy, narrow-band imaging is not suggested is place of white-light colonoscopy (conditional recommendation, low-quality evidence)

5.

When performing surveillance with high-definition colonoscopy, narrow-band imaging is not suggested in place of white-light colonoscopy (conditional recommendation, moderate-quality evidence)

6.

When performing surveillance with image-enhanced high-definition colonoscopy, narrow-band imaging is not suggested in place of chromoendoscopy (conditional recommendation, moderate-quality evidence)
 
Management of dysplasis discovered on surveillance colonoscopy

7.

After complete removal of endoscopically resectable polypoid dysplastic lesions, surveillance colonoscopy is recommended rather than colectomy (strong recommendation, very low-quality evidence)

8.

After complete removal of endoscopically resectable nonpolypoid dysplastic lesions, surveillance colonoscopy is suggested rather than colectomy (conditional recommendation, very low-quality evidence)

9.

For patients with endoscopically invisible dysplasis (confirmed by a Gl pathologist) referral is suggested to an endoscopist with expertise in IBD surveillance using chromoendoscopy with high-definition colonoscopy (conditional recommendation, very low-quality evidence)

Other techniques for image-enhanced endoscopy are under investigation. Narrow-band imaging (NBI), an optical chromoendoscopy technology that uses filters to enhance the contrast of the mucosa and vasculature has not demonstrated an increased yield for dysplasia detection in randomized studies comparing NBI to either standard definition white light endoscopy (WLE) or high definition WLE [8689]. Studies comparing NBI with chromoendoscopy have reported a numerically higher detection rate with chromoendoscopy but at meta-analysis the difference was not statistically significant. The SCENIC consensus, therefore, does not recommend NBI over dye spray chromoendoscopy [68]. Autofluorescence and confocal laser endomicroscopy are under study but current data do not support their routine use [5, 68].



Dysplasia


Detection of dysplasia is the immediate goal of surveillance colonoscopy and in turn the best marker of CRC risk in IBD patients although its detection has not clearly been documented to improve clinical outcomes such as CRC incidence or mortality [68]. Biopsies taken at surveillance colonoscopy must be graded as (1) positive for dysplasia, (2) negative for dysplasia, or (3) indefinite for dysplasia. These are further classified as (1) low-grade dysplasia (LGD), (2) high-grade dysplasia (HGD ), or (3) carcinoma [90]. There is considerable inter-observer variability amongst pathologists around interpretation of low-grade dysplasia and “indefinite for dysplasia” categories [91]. Thus, once dysplasia is detected, a second opinion should be obtained from a specialist gastrointestinal pathologist to confirm the diagnosis [91].

Dysplasia is characterized as an endoscopically visible dysplastic lesion detected via targeted biopsies or via resection or indeed endoscopically invisible dysplasia detected by random biopsies [5]. Older guidelines recommended characterizing detected lesions as sporadic adenomas if found outside an area of known colitis or as dysplasia-associated lesion or mass (DALM) if detected within an area of colitis [10]. DALM’s were further sub characterized as adenoma like (if raised or had an endoscopic appearance of a sporadic adenoma), or non-adenoma like [2]. Adenoma like DALM’s were amenable to endoscopic resection with close follow-up, whereas non-adenoma like DALM’s were an indication for surgery, with colectomy being traditionally indicated for high-grade dysplasia detected by random biopsy and multifocal low-grade dysplasia detected at random biopsies [2]. Recent guidelines recommend that the terms DALM , adenoma-like, and non-adenoma like lesion should be abandoned with the addition of terms for ulceration and border of the lesion [48, 68, 80, 92]. Thus, the term endoscopically resectable indicates that (1) distinct margins lesion can be identified, (2) lesion appears completely excised on visual inspection after endoscopic resection, (3) histological assessment of the restricted specimen is consistent with complete removal, and (4) biopsy specimens taken from mucosa immediately adjacent to the resection site are free of dysplasia on histological assessment [68]. Figures 60.1, 60.2, and 60.3 are examples of pseudopolyps, polypoid dysplasia, and non-polypoid dysplasia respectively.

A210762_2_En_60_Fig1_HTML.jpg


Fig. 60.1
Pseudopolyp


A210762_2_En_60_Fig2_HTML.jpg


Fig. 60.2
Polypoid dysplasia


A210762_2_En_60_Fig3_HTML.jpg


Fig. 60.3
Non-polypoid dysplasia


Management of Dysplasia


The ability to accurately identify dysplasia and determine its potential resectability is key to further management [68]. The use of chromoendoscopy and other image enhancing techniques have enhanced dysplasia detection and lesion delineation as described above. Lesion morphology should be described as being polypoid (pedunculated or sessile) or non-polypoid (slightly elevated, flat, or depressed) and lesion borders classified as distinct or indistinct [5, 68, 93]. Any presence of overlying ulceration or features of sub mucosal invasion (such as depression or failure to lift with submucosal injection) may be indicative of underlying malignancy [80].

A lesion detected at endoscopy should be identified as being within or outside an area of known colitis. Lesions in segments outside an area of known colitis should be treated as sporadic adenomas with standard post-polypectomy surveillance recommendations [2, 48, 94, 95]. Lesions in an area of known colitis should be assessed for endoscopic resectability and if possible completely resected by an experienced endoscopist regardless of underlying colitis or grade of dysplasia, acknowledging that inflammation, friability and scarring can make such resection technically more difficult in which case tattooing and photo documentation should be considered to aid subsequent surveillance or resection [5, 48, 68]. Colonic mucosa adjacent to the raised lesion should also be biopsied to evaluate for dysplasia and if complete resection is achieved with dysplasia free margins and no invisible dysplasia elsewhere in the colon, surveillance colonoscopy is recommended rather than colectomy [48, 68]. ECCO recommends surveillance with chromoendoscopy at 3 months and then at least annually whereas US Multi-Society guidelines suggest a 3–6 month check for larger sessile lesions removed in piecemeal fashion or via EMR or ESD with longer surveillance intervals if the initial repeat colonoscopy result is negative [94, 95]. Long-term follow-up studies of endoscopically resectable polypoid lesions are reassuring demonstrating a low risk of developing dysplasia or carcinoma over follow-up [96100]. A recent meta-analysis also demonstrates a low risk of IBD-CRN following resection of polypoid dysplasia [101]. Indeed patients diagnosed with dysplasia themselves are more likely to refuse or delay colectomy and prefer surveillance colonoscopy [68]. A recent study showed that patients would agree to immediate colectomy only when the risk of synchronous CRC rose to above 73 % [72].

Management of non-polypoid dysplastic lesions is more challenging. Two studies have demonstrated high cure rates after complete resection of circumscribed lateral spreading lesions and lesions with high-grade dysplasia (HGD) [102, 103]. The SCENIC consensus supports surveillance colonoscopy after complete removal of endoscopically resectable non-polypoid dysplastic lesions [68]. This recommendation is conditional recognizing the higher CRC risk and greater endoscopic difficulty with resectability conferred by non-polypoid lesions. Other recent guidelines recommend colectomy for non-polypoid dysplastic lesions because they considered such lesions generally not amenable to endoscopic resection [2, 8, 9].

The management of endoscopically invisible dysplasia detected by random biopsies alone has evolved considerably. Invisible dysplasia was defined in the SCENIC paper as dysplasia identified on random (nontargeted) biopsies of colon mucosa without a visible lesion. Data from St Mark’s Hospital indicates that 20 % of patients with flat LGD detected by random biopsies had CRC at the time of immediate colectomy [28]. Ullman et al. found synchronous advanced lesions including flat HGD or CRC in 23 % of patients undergoing colectomy for flat LGD detected on random biopsies [24]. A systematic review of 20 studies and 477 patients with invisible low-grade dysplasia found that 22 % of patients with invisible low-grade dysplasia who had colectomy had CRC [104]. Other studies however have challenged this rate of progression [105107]. One study showed a 3 % initial and 10 % subsequent rate of progression from LGD to CRC in a 10-year period. Recognition that most dysplasia is visible and evolution in endoscopic technology suggest that random biopsies showing invisible dysplasia in previous studies may have been taken from previously unrecognizable lesions that can now be visualized with modern endoscopic techniques [68]. More recent studies of chromoendoscopy or high-definition white light colonoscopy have reported a 10 % incidence of invisible dysplasia [68]. The AGA recommends colectomy for multifocal flat LGD [2]. The BSG also considers colectomy the best option for LGD but suggests chromoendoscopy if there is uncertainty with the diagnosis and regular surveillance for patients who decline colectomy [6]. The SCENIC consensus supports confirmation of dysplasia by a second GI pathologist and referral to an endoscopist with expertise in IBD surveillance and chromoendoscopy and with high-definition to better inform subsequent decisions regarding surveillance versus colectomy [68]. If a visible dysplastic lesion is identified in the same region of the colon as the invisible dysplasia and the lesion can be resected endoscopically, such patients may remain in a surveillance program. If dysplasia is not found, individualized discussions involving the risks and benefits of surveillance versus colectomy are suggested [68].

Colectomy is the treatment of choice when flat HGD is confirmed by a second GI pathologist or incompletely resected raised dysplasia is discovered. In a review from 1992 of ten prospective surveillance trials including 1225 patients, the prevalence of synchronous CRC in patients with flat HGD was 42 % [15]. In the St Mark’s study of 600 patients in a surveillance program over 30 years, 45.5 % of patients with flat HGD detected on random biopsies who underwent immediate colectomy had evidence of CRC in the colectomy specimen. Of those who deferred colectomy and continued surveillance, 25 % later developed CRC [28]. Given the high rate of synchronous carcinomas, colectomy is indicated when flat HGD is found [2]. An endoscopically unresectable lesion or a lesion with dysplasia in the adjacent mucosa is an indication for colectomy [5, 48, 68, 80].

In the presence of chronic active inflammation it is difficult to distinguish regeneration and repair from dysplasia frequently resulting in a pathological finding that is indefinite for dysplasia . Less is known about its significance in assessing CRC risk. In a study of 56 patients with biopsies indefinite for dysplasia, a 9 % 5-year progression rate to HGD or CRC was observed [24]. Aggressive treatment of the underlying inflammation followed by endoscopic reevaluation preferably with chromoendoscopy is recommended [5, 33]. Since the risk of progression to CRC is higher compared to no dysplasia, a follow-up surveillance examination should take place within 3–6 months [2]. See Table 60.4 for a summary of societal guidelines for the management of dysplasia detected at endoscopic surveillance . The updated 2015 algorithm suggested by the American Society for Gastrointestinal Endoscopy for endoscopically visible lesions is shown in Table 60.5.


Table 60.4
Society guidelines for detected dysplasia

























































 
Visible dysplastic lesion, endoscopically resectable with negative biopsies from adjacent mucosa

Visible dysplastic lesion, endoscopically unresectable, or biopsies from adjacent mucosa with dysplasia

Invisible high-grade dypslasia detected by random biopsies

Invisible low-grade dysplasia detected by random biopsies

ECCO,8 2013

Surveillance at 3 months and then yearly, regardless of degree of dysplasia

Colectomy

Confirm by expert GI pathologist

Rule out visible lesion with repeat chromoendoscopy surveillance

Colectomy if confirmed

Confirm by expert GI pathologist

Rule out visible lesion with chromoendoscopy surveillance

Consider colectomy vs. intensified surveillance with random biopsies

CCA,9 2011

Surveillance

Colectomy

Confirm by expert GI pathologist

Colectomy

Confirm by expect GI pathologist

Multifocal: colectomy vs. intensified surveillance at 3–6 months with chromoendoscopy, then annually

Unifocal: consider surgery vs. surveillance at 6 months then annually

BSG,1 2010

Surveillance

Colectomy

Not specifically mentioned

Confirm by expect GI pathologist

Consider colectomy vs. intensified surveillance

ACG,4 2010

Surveillance

Colectomy

Confirm by expert GI pathologist

Colectomy

Confirm by expert GI pathologist

Colectomy vs. intensified surveillance

AGA,2 2010

Adenoma-like DALM : surveillance (6 months)

Non-adenoma-like DALM : colectomy

Confirm by expert GI pathologist

Colectomy

Confirm by expert GI pathologist

Colectomy vs. intensified surveillance

ASGE,5 2006

Surveillance

DALM : colectomy

Confirm by expert GI pathologist

Colectomy

Confirm by expert GI pathologist

Mutlifocal: colectomy

Unifocal: consider colectomy vs. surveillance at 6 months then annually

CCFA,3 2005
     
Confirm by expert GI pathologist

Multifocal or repetitive: colectomy

Unifocal: colectomy: if patient opts for surveillance, then <6-month intervals recommended

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Jun 27, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Incidence of Cancer and Screening in Inflammatory Bowel Disease

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