Expert Review of Anticancer Therapy
ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20
Colorectal cancer in inflammatory bowel disease: a shift in risk? Zane R Gallinger & Adam V Weizman To cite this article: Zane R Gallinger & Adam V Weizman (2014) Colorectal cancer in inflammatory bowel disease: a shift in risk?, Expert Review of Anticancer Therapy, 14:7, 847-856 To link to this article: http://dx.doi.org/10.1586/14737140.2014.895936
Published online: 13 Mar 2014.
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Colorectal cancer in inflammatory bowel disease: a shift in risk? Downloaded by [University of Pennsylvania] at 13:07 05 November 2015
Expert Rev. Anticancer Ther. 14(7), 847–856 (2014)
Zane R Gallinger1 and Adam V Weizman*1,2 1 Department of Medicine, University of Toronto, Toronto, Ontario, Canada 2 Division of Gastroenterology, Women’s College Hospital, University of Toronto, 76 Grenville St, 4th Floor, Toronto, Ontario, Canada *Author for correspondence: Tel.: +1 416 323 7543 Fax: +1 416 323 7549 [email protected]
Patients with inflammatory bowel disease are at an increased risk for the development of colorectal cancer. However, the magnitude of this risk may not be as high as earlier studies have suggested. This shift in risk may be a result of changes in quality of analyses, aging cohorts, or may indeed represent true declines in the risk of cancer as a result of improvements in medical therapy and surveillance programs. The best surveillance practices for colorectal cancer screening in patients with inflammatory bowel disease remains unclear. The finding of dysplasia on colonoscopy in these patients warrants multi-disciplinary consultation between endoscopist, pathologist, and patient. At present, major organizations offer guidelines for surveillance interval, as well as when surgical consultation is advised. Moreover, newer endoscopic technologies have been developed and their incorporation into dysplasia surveillance programs continues to evolve. KEYWORDS: chromoendoscopy • Crohn’s disease • dysplasia • endoscopy • inflammatory bowel disease • surveillance • ulcerative colitis
Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition characterized by relapsing inflammation. There are two main subtypes of IBD: ulcerative colitis (UC) and Crohn’s disease (CD). The risk of colorectal cancer (CRC) in patients with IBD has been studied extensively over the decades. Patients with IBD involving their colon, particularly those with UC, are thought to be at an increased risk of CRC secondary to prolonged inflammatory states that transform inflamed mucosa into dysplasia, and subsequently, invasive adenocarcinoma [1,2]. Chronic inflammation allows for malignant cells to proliferate, creates an environment that promotes angiogenesis and malignant spread and can inhibit natural immune processes through the augmentation of cytokine and transcription factor function [2–4]. Studies have shown that when NF-kB, a transcription factor found in all animal cells, is exposed to mediators of inflammation, it can become an endogenous promoter of colon carcinogenesis. Specifically, in animal studies, it has been implicated in the initiation of tumor growth and progression [5]. Multiple studies have shown an increased relative risk (RR) of CRC in patients with
informahealthcare.com
10.1586/14737140.2014.895936
colonic IBD; however, the absolute risk varies considerably in the literature and much uncertainty remains over the lifetime probability of CRC as well as the most effective surveillance program [6–10]. In this article, we review the literature on the magnitude of CRC risk in IBD and the current surveillance recommendation. We also outline several new surveillance tools available. CRC risk in UC
Many factors have been associated with increased risk of CRC in UC. These include disease duration, location, associated extraintestinal features such as primary sclerosing cholangitis (PSC) and family history of CRC. In general, individuals with extensive mucosal involvement over a long duration, defined in most studies as involvement of over 50% of the mucosa and duration of disease over 10 years, have an increased standardized incident ratio for developing CRC [11–13]. For example, a meta-analysis reported that the lifetime risk of CRC among patients with UC increases from 3.7 to 5.4% with pancolitis, compared with left-sided colitis. The same study showed that UC incidence rates increases
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Gallinger & Weizman
in a stepwise fashion from the time of original diagnoses, with an increase of 2% after 10 years, 8% after 20 years and 18% after 30 years [14]. Data on an increased risk in left-sided colitis (defined as colitis limited to the area distal to the splenic flexure) are less clear with some studies suggesting risks similar to pancolitis [15]. Proctitis and ulcerative proctosigmoiditis are not associated with increased risk of CRC. Histologic signs of inflammation may be an indicator of increased CRC risk, with more inflammation on biopsy specimens correlating with an increased RR of dysplasia in some studies [16]. One case–control study determined a positive correlation between endoscopic (odds ratio [OR]: 2.5; p < 0.0001) and histological (OR: 5.1; p < 0.001) inflammation with increased neoplastic risk [16]. Similarly, a cohort study by Gupta et al. found a positive relationship between histological inflammation and the chance of progression to neoplasia (hazard ratio: 3.0; 95% CI: 1.4–6.3) [17]. These studies would, therefore, suggest that histologic involvement may be a more important predictor of neoplasia than endoscopically evident inflammation, which supports the importance of defining disease extent by histologic activity that is usually more extensive than what is appreciated on colonoscopy [18]. It is important to highlight that the presence of active disease at the time of colonoscopy can confound the pathologic interpretation of dysplasia. Reactive epithelium in the setting of active UC can share certain histologic features with true dysplasia, making the pathologist’s interpretation difficult [19]. These biopsies are often classified as ‘indefinite for dysplasia’ (see later). Therefore, surveillance colonoscopy should ideally be performed at a time when endoscopic disease activity is minimal [18]. As mentioned above, there are other features that can further increase the risk of dysplasia and cancer in patients with UC, in addition to disease extent, activity or duration. PSC is a well-established risk factor. Jess et al. found that UC patients with PSC compared with patients without PSC were at significantly increased risk of developing CRC (RR: 9.13; 95% CI: 4.52–18.5) [10]. Another population-based study determining the prevalence of PSC among patients with UC requiring proctocolectomy was higher than the general UC population [20]. Family history of previous CRC is also a well-defined risk factor for UC patients progressing to dysplasia. As a result, multiple guidelines suggest that those UC patients with a first-degree relative diagnosed with CRC before 50 years of age be classified as high risk, and therefore should receive annual colonoscopy, as is the recommendation for those with PSC [21–23]. CRC risk in CD
Wide variations have been reported for the risk of CRC in patients with CD compared with those with UC [24–27]. Nonetheless, most studies show that colonic CD patients are likely at an increased risk for CRC compared with age-matched average risk populations [28]. One meta-analysis reported a 2.5-fold (95% CI: 1.3–4.7) increased RR in patients with colonic CD, compared with those with isolated ileal disease only (1.1 [95% CI: 0.8–1.5]) [29]. More data are needed to better characterize 848
dysplasia risk in Crohn’s colitis; however, the signals to date suggest these patients should be approached similarly to those with UC [7,9]. Changes in magnitude of risk
Early population-based studies demonstrated an increased risk of malignancy with IBD, specifically UC [13,28,30–33]. Follow-up studies from these early reports have reaffirmed an elevated risk of CRC in IBD, however, the magnitude of risk may not be as high as initially thought. Rates from these studies may have been artificially elevated for several reasons, including the use of data from referral centers, the inclusion of case reports and differences in inclusion and exclusion criteria. A recent metaanalysis demonstrated a pooled standardized incidence ratio of CRC in IBD patients of only 1.7 (95% CI: 1.2–2.2) [34]. A smaller cohort study from Copenhagen determined that the risk of developing CRC in patients with IBD over 19 years was not elevated. The authors speculated this finding was due to active surveillance programs, early colectomy as well as the use of 5-aminosalicyic acid (ASA) for treatment relapse, a topic that remains controversial [35]. Lutgens et al. suggested the decreased magnitude of risk is an artifact of an aging cohort [34] and suspected that reanalysis of older cohort studies are limited, since only a few new IBD patients have been added to the initial cohort, which have already had the highest-risk patients develop CRC. This results in a marginal change to the number of people at risk and therefore a lower risk ratio. It is also possible that medical and surgical interventions, such as improved surveillance, increased colectomy rates and better medical management have caused a true decline in CRC rates in IBD [36–39]. For example, a Swedish cohort study found that risk of dying from CRC for patients with IBD has decreased significantly over the past 35 years [40]. Other studies have found similar results, suggesting a decline in CRC rates in patients diagnosed with IBD [9,10,34]. The contribution of medical therapy on this observed decline in risk is interesting, but remains unclear. One meta-analysis, which analyzed nine studies, displayed a protective association with the use of 5-ASA and CRC risk (OR: 0.51; 95% CI: 0.37–0.69), the theory being decreased inflammation is protective [41]. However, a more recent meta-analysis evaluating the chemoprotective characteristics of 5-ASA therapy did not show any significant benefit [42]. Among patients with PSC and UC, data from a randomized controlled study and a cross-sectional study demonstrated a reduced risk of dysplasia with use of ursodeoxycholic acid, suggesting a cytologic protective role for this bile acid [43,44]. Furthermore, treatment modalities have changed significantly since early publications of CRC risk estimates and the impact of immunomodulators such as azathioprine, methotrexate and biologic therapy with anti-TNFs on observed declines in dysplasia need to be further elucidated [45]. Detecting dysplasia
Detecting dysplasia in the colon is the principal goal of IBD surveillance programs. One of the major challenges of dysplasia Expert Rev. Anticancer Ther. 14(7), (2014)
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CRC in IBD
surveillance is that while dysplasia may occur in endoscopically visible mucosal abnormalities (e.g., polyps, nodules or masses), referred to as dysplasia-associated lesions or masses (DALMs), it can also occur in relatively flat lesions that may not be appreciated at the time of colonoscopy and detected only in random biopsies. This lesion has been referred to as ‘flat dysplasia’. With the improvements in the quality of endoscopic images and development of new surveillance tools (discussed below), endoscopists have now been able to become even more descriptive in the description of the morphology of these lesions. This has culminated in the development of the Paris classification of neoplastic lesions, which should be used routinely in reporting [46]. A classification system for dysplasia was developed by a collaborative group of pathologists in 1983, which subdivided dysplasia as negative, indefinite or positive [47]. The Vienna Classification has more recently been developed to better characterize dysplasia and provide clinical relevance to the histologic findings [48]. Using this system, dysplasia is further subclassified as either indefinite for dysplasia/neoplasia, low-grade dysplasia/ neoplasia, high-grade dysplasia/neoplasia or invasive neoplasia. Detecting dysplasia is important as not only does the dysplastic focus detected have the potential to evolve into or may already harbor adenocarcinoma, but it may also be an indicator of dysplasia or adenocarcinoma elsewhere in the colon. Colectomy specimens of patients with UC who have low- and high-grade dysplasia have been associated with an increased likelihood of adenocarcinoma. Patients with high-grade dysplasia have been shown to have a synchronous colon cancer at the time of colectomy in 40–50% of cases [7,9]. The association of low-grade dysplasia with co-existing or progression to adenocarcinoma is less clear and has ranged in the literature from 10 to 50% of cases [49,50]. One retrospective study of pathology reports found endoscopic evidence of low-grade dysplasia has positive predictive value of 70% for finding a synchronous cancer [51]. The association between dysplasia and CRC risk is likely similar in CD [29,52]. Indefinite neoplasia/dysplasia, as discussed above, is often noted when surveillance is performed at the time of disease activity, which creates challenges in differentiating changes typical of reactive epithelium and dysplasia. As in the general population, patients with IBD can also develop sporadic adenomas. These can often create a challenge in management as it is occasionally difficult to differentiate disease-associated dysplasia, as described above, and sporadic dysplasia in an adenoma that may have evolved independent of the underlying IBD. This distinction is usually made based on the appearance of the lesion at colonoscopy. Penduculated or sessile polyps are more likely to be typical of sporadic adenomas commonly seen in non-IBD patients and are therefore referred to as ‘adenoma-like DALMs’. Ulcerated, flat or plaque-like lesions are often considered more irregular and less likely to be that of a typical sporadic adenoma and have therefore been termed ‘non-adenoma-like DALMs’ [37,53]. The former are often managed according to general CRC screening guidelines and removed endoscopically, whereas diseaseassociated dysplasia warrants colectomy, closer surveillance or informahealthcare.com
Review
endoscopic mucosal resection. A multidisciplinary approach involving the endoscopist, pathologist and patient is needed in making a therapeutic plan with consideration of clinical factors including disease duration, distribution, PSC or a family history of CRC [54,55]. It is evident that the current histologic and endosopic classification systems do have some shortcomings. Much of these systems are subjective and therefore susceptible to interobserver variability, a finding that has been confirmed in several studies in the literature [56,57]. The difference between high- and low-grade dysplasia can significantly impact the treatment plan and therefore should be reviewed and confirmed by an expert [58]. For example, patients with low-grade dysplasia often require a careful review with a multidisciplinary team to decide whether or not to proceed with surgery [59]. It is therefore imperative that pathologists with extensive experience scrutinize biopsies so that patients and physicians are able to make the most informed decisions. Managing dysplasia
The optimal surveillance methods for CRC in patients with IBD remain unclear. Several confounding factors and a lack of randomized controlled trials contribute to the inability to determine the best methods of detecting CRC and its precursors among IBD patients. A Cochrane review determined that there was no clear evidence that surveillance colonoscopy increased survival. In their pooled analysis, 7% of patients in the surveillance group compared with 11% of patients in the non-surveillance group died from CRC, respectively (RR: 0.81; 95% CI: 0.17–3.83) [60]. However, this review also demonstrated indirect evidence that surveillance reduces the risk of death from CRC in patients with IBD by detecting cancer earlier. Furthermore, data from case– control studies, retrospective studies and meta-analyses have led to consensus guidelines for surveillance, and despite the weak evidence in support of colonoscopy surveillance, most endoscopists do subscribe to this practice. The goal of surveillance is to detect dysplasia so that appropriate stratification can be made to determine subsequent treatment steps. It is generally accepted that patients with flat high-grade dysplasia should undergo colectomy because of the high rates of progression to or coexisting CRC [21,22,61]. Those patients with multifocal flat dysplasia should also be considered for proctocolectomy [62–64]. Low-grade unifocal dysplasia remains more controversial. Weinstein et al. suggested that given the inherent error in surveillance techniques and the significance of being diagnosed with CRC, all patients with dysplasia (including unifocal low-grade dysplasia) who are willing and able should undergo colectomy [7]. However, the unclear magnitude of risk of progression of low-grade dysplasia as mentioned above as well the fact that dysplasia can be overcalled during times of disease activity warrants careful consideration and a multidisciplinary review prior to finalizing a management plan [58]. Conversations with patients should include the discussion of risks and benefits of surgery versus that of ongoing surveillance, which may fail to detect occult malignancy. One medical decision analysis for patients with unifocal flat 849
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low-grade dysplasia suggested a benefit in quality of life and lower costs among patients who chose immediate proctocolectomy over intensive surveillance [49]. If a DALM is seen on initial surveillance colonoscopy, multiple biopsies should be taken throughout the entire colon. Current guidelines suggest that all IBD patients with non-adenoma DALMs should undergo colectomy [65]. As mentioned previously, patients with adenoma-like DALMs need a thorough clinical review when determining whether to proceed with colectomy. Evidence exists that these patients can be managed successfully with complete polypectomy and continued surveillance, much like the general population [53]. A unique situation is in UC patients with colonic strictures, as these are considered a high risk of developing CRC and colectomy is often indicated. If biopsies of a stricture show no evidence of dysplasia and a decision is made to continue with ongoing surveillance, very close and cautions monitoring is required [55]. Major organization surveillance guidelines
Multiple organizations have created specific guidelines for CRC surveillance in patients with IBD. TABLE 1 summarizes the recommendations from the American Gastroenterology Association [18,65], the American Society for Gastrointestinal Endoscopy [64,66], the British Society of Gastroenterology [21,61], the American College of Gastroenterology [62,63] and more recently the European Crohn’s and Colitis Organization [22]. These new guidelines expand on some of the discordant recommendations of previous guidelines. In addition, recommendations about the use of chromoendoscopy (CE) are discussed. Surveillance programs for CD often mimic those that have used data from UC patients. Expert commentary
Dysplasia surveillance is a critical component of providing high-quality care to patients with IBD. While the evidence in support of its impact on decreasing mortality from CRC is unclear, most providers have routinely incorporated it into practice [67]. These patients have been consistently shown to be at increased risk of CRC compared with the general population, and most physicians see death from CRC in patients with IBD as an unacceptable outcome. However, the magnitude of risk of CRC in this population may be changing, likely due to both changing methodologies in evaluating IBD cohorts as well as improved medical therapy, widespread dissemination of dysplasia surveillance guidelines and earlier referral for colectomy. Our IBD patients have been shown to be insufficiently informed regarding long-term risk of disease, including CRC risk, and in order to provide high-quality, patient-centered care, more clarity on the true magnitude of risk and best methods to potentially reduce this risk is needed [68]. Although major organizations have developed IBD/CRC surveillance guidelines, and while the core suggestions remain similar, incongruence has left physicians uncertain [69]. A proactive effort in increasing future study that may provide more data on the actual CRC risk in IBD and the impact of surveillance in 850
augmenting this risk is essential. Moreover, the impact of newer technologies that may replace random colonic segment biopsies holds promise for improving efficiencies and possibly cost of surveillance and warrants close evaluation. Five-year view
The past few decades have witnessed the introduction of new equipment and techniques designed to enhance the detection of dysplasia on endoscopy. Of note, among the most widely studied imaging techniques, CE may provide a higher diagnostic yield of detecting dysplasia. CE allows the endoscopist to apply stains such as methylene blue or cresyl violet or contrast agents such as indigo carmine to the mucosa, with the goal of identifying areas of flat dysplasia or mucosal abnormalities that would be otherwise missed with conventional, white-light colonoscopy. Randomized controlled trials have shown that CE is superior to standard white-light endoscopy techniques [70,71]. A meta-analysis by Subramanian et al. found an increase in detection of dysplasia with CE compared with white light of 7% (95% CI: 3.2–11.3), with a number needed to treat of 14.3 [72]. Using the Kudo pit system, gastroenterologists were able to increase their detection of dysplastic mucosa and subsequently reduce the number of biopsies for adequate surveillance [73]. The success of CE has resulted in an increasing number of gastroenterologists incorporating this technique into their practice, leading some to advocate its incorporation [74] into routine surveillance programs [22,61,64]. However, the need for more evidence in support, the relatively longer time and training required to perform the procedure and the requirement of excellent bowel preparation has limited its widespread use. Narrow band imaging (NBI) is another novel technique that allows increased resolution of mucosa without dyes. It has been evaluated for IBD surveillance programs. Controversy exists whether NBI should be routinely used in surveillance programs, as some studies demonstrate increased miss rates with NBI compared with CE [75,76]. Other studies revealed equivalence between NBI and CE in detecting dysplasia (18.5 vs 16.7%, respectively; p = 0.068) [77]. One meta-analysis of eight studies found that NBI with magnification had a high diagnostic accuracy for characterizing high-grade dysplasia, potentially improving the yield of targeted biopsies [78]. Similarly, a metaanalysis by Wu et al. of 11 studies demonstrated NBI has high diagnostic precision for detecting colorectal neoplasia [79]. Continued randomized controlled trials of these new imaging techniques will allow major organizations to determine their role in surveillance programs. Other new techniques being explored include virtual CE, confocal laser endomicroscopy (CFE), autofluorescence imaging and endocytoscopy. When combined with CE, CFE allows the viewer to see live in vivo histopathology, with 1000-fold magnification of the tissue [80]. CFE is becoming a well-established option for the early detection of dysplasia, with one study showing a 4.75-times increased neoplasia detection rate (p = 0.005) with CFE and CE together compared with CE Expert Rev. Anticancer Ther. 14(7), (2014)
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Colectomy with flat dysplasia
Need assessment with patient
High grade
Low grade
Colectomy with flat, multifocal dysplasia Unifocal – need individualized risk assessment with patient
Colectomy with flat, multifocal dysplasia
Urgent repeat chromoendoscopy to assess for associated endoscopically visible lesions to resect, and if not then colectomy Multidisciplinary, detailed team discussion with patient to decide if to proceed with a colectomy OR potential for chromoendoscopic colonoscopy with additional random biopsies within 3 months Need individualized risk assessment with patient Colectomy should be considered with flat dysplasia
If polypectomy is complete by histology, and biopsies from flat mucosa adjacent show no dysplasia and there are no other areas of dysplasia, close follow up with chromoendoscopy at 3 months and then annual surveillance is recommended Colectomy with flat dysplasia
Colectomy
Pan-colonic methylene blue or indigo carmine chromoendoscopy with targeted biopsies of visible lesion If chromoendoscopy not available, random biopsies (4 every 10 cm) should be performed, however, this is inferior to detecting neoplastic lesions
Same as average risk
8–10 years
8–10 years
ECCO
Colectomy with flat dysplasia
Colectomy
Pancolonic dye spraying If no chromoendoscopy used, 2–4 samples every 10 cm of entire colon and extra for suspicious areas
Multiple biopsies
Four quadrants every 10 cm from cecum to rectum for 32 total Suspicious lesions
Colectomy
Not mentioned
15–20 years
8–10 years
BSG
8–10 years
8–10 years
8–10 years
ACG
Same as average risk
15 years
8–10 years
ASGE
‡
For ECCO guidelines, all visible lesions with dysplasia should be completely resected by an experienced endoscopist, irrespective of location and grade. Definition of risk as per BSG guidelines – High risk: Extensive with moderate/severe active endoscopic/histological inflammation or stricture in past 5 years or dysplasia in past 5 years and declining surgery or primary sclerosing cholangitis or family history of colorectal cancer at age less than 50 years; Intermediate risk: Extensive colitis with mild active endoscopic/histological inflammation or post-inflammatory polyps or family history of colorectal cancer diagnosed at age
ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: http://www.tandfonline.com/loi/iery20
Colorectal cancer in inflammatory bowel disease: a shift in risk? Zane R Gallinger & Adam V Weizman To cite this article: Zane R Gallinger & Adam V Weizman (2014) Colorectal cancer in inflammatory bowel disease: a shift in risk?, Expert Review of Anticancer Therapy, 14:7, 847-856 To link to this article: http://dx.doi.org/10.1586/14737140.2014.895936
Published online: 13 Mar 2014.
Submit your article to this journal
Article views: 31
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iery20 Download by: [University of Pennsylvania]
Date: 05 November 2015, At: 13:07
Review
Colorectal cancer in inflammatory bowel disease: a shift in risk? Downloaded by [University of Pennsylvania] at 13:07 05 November 2015
Expert Rev. Anticancer Ther. 14(7), 847–856 (2014)
Zane R Gallinger1 and Adam V Weizman*1,2 1 Department of Medicine, University of Toronto, Toronto, Ontario, Canada 2 Division of Gastroenterology, Women’s College Hospital, University of Toronto, 76 Grenville St, 4th Floor, Toronto, Ontario, Canada *Author for correspondence: Tel.: +1 416 323 7543 Fax: +1 416 323 7549 [email protected]
Patients with inflammatory bowel disease are at an increased risk for the development of colorectal cancer. However, the magnitude of this risk may not be as high as earlier studies have suggested. This shift in risk may be a result of changes in quality of analyses, aging cohorts, or may indeed represent true declines in the risk of cancer as a result of improvements in medical therapy and surveillance programs. The best surveillance practices for colorectal cancer screening in patients with inflammatory bowel disease remains unclear. The finding of dysplasia on colonoscopy in these patients warrants multi-disciplinary consultation between endoscopist, pathologist, and patient. At present, major organizations offer guidelines for surveillance interval, as well as when surgical consultation is advised. Moreover, newer endoscopic technologies have been developed and their incorporation into dysplasia surveillance programs continues to evolve. KEYWORDS: chromoendoscopy • Crohn’s disease • dysplasia • endoscopy • inflammatory bowel disease • surveillance • ulcerative colitis
Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition characterized by relapsing inflammation. There are two main subtypes of IBD: ulcerative colitis (UC) and Crohn’s disease (CD). The risk of colorectal cancer (CRC) in patients with IBD has been studied extensively over the decades. Patients with IBD involving their colon, particularly those with UC, are thought to be at an increased risk of CRC secondary to prolonged inflammatory states that transform inflamed mucosa into dysplasia, and subsequently, invasive adenocarcinoma [1,2]. Chronic inflammation allows for malignant cells to proliferate, creates an environment that promotes angiogenesis and malignant spread and can inhibit natural immune processes through the augmentation of cytokine and transcription factor function [2–4]. Studies have shown that when NF-kB, a transcription factor found in all animal cells, is exposed to mediators of inflammation, it can become an endogenous promoter of colon carcinogenesis. Specifically, in animal studies, it has been implicated in the initiation of tumor growth and progression [5]. Multiple studies have shown an increased relative risk (RR) of CRC in patients with
informahealthcare.com
10.1586/14737140.2014.895936
colonic IBD; however, the absolute risk varies considerably in the literature and much uncertainty remains over the lifetime probability of CRC as well as the most effective surveillance program [6–10]. In this article, we review the literature on the magnitude of CRC risk in IBD and the current surveillance recommendation. We also outline several new surveillance tools available. CRC risk in UC
Many factors have been associated with increased risk of CRC in UC. These include disease duration, location, associated extraintestinal features such as primary sclerosing cholangitis (PSC) and family history of CRC. In general, individuals with extensive mucosal involvement over a long duration, defined in most studies as involvement of over 50% of the mucosa and duration of disease over 10 years, have an increased standardized incident ratio for developing CRC [11–13]. For example, a meta-analysis reported that the lifetime risk of CRC among patients with UC increases from 3.7 to 5.4% with pancolitis, compared with left-sided colitis. The same study showed that UC incidence rates increases
2014 Informa UK Ltd
ISSN 1473-7140
847
Downloaded by [University of Pennsylvania] at 13:07 05 November 2015
Review
Gallinger & Weizman
in a stepwise fashion from the time of original diagnoses, with an increase of 2% after 10 years, 8% after 20 years and 18% after 30 years [14]. Data on an increased risk in left-sided colitis (defined as colitis limited to the area distal to the splenic flexure) are less clear with some studies suggesting risks similar to pancolitis [15]. Proctitis and ulcerative proctosigmoiditis are not associated with increased risk of CRC. Histologic signs of inflammation may be an indicator of increased CRC risk, with more inflammation on biopsy specimens correlating with an increased RR of dysplasia in some studies [16]. One case–control study determined a positive correlation between endoscopic (odds ratio [OR]: 2.5; p < 0.0001) and histological (OR: 5.1; p < 0.001) inflammation with increased neoplastic risk [16]. Similarly, a cohort study by Gupta et al. found a positive relationship between histological inflammation and the chance of progression to neoplasia (hazard ratio: 3.0; 95% CI: 1.4–6.3) [17]. These studies would, therefore, suggest that histologic involvement may be a more important predictor of neoplasia than endoscopically evident inflammation, which supports the importance of defining disease extent by histologic activity that is usually more extensive than what is appreciated on colonoscopy [18]. It is important to highlight that the presence of active disease at the time of colonoscopy can confound the pathologic interpretation of dysplasia. Reactive epithelium in the setting of active UC can share certain histologic features with true dysplasia, making the pathologist’s interpretation difficult [19]. These biopsies are often classified as ‘indefinite for dysplasia’ (see later). Therefore, surveillance colonoscopy should ideally be performed at a time when endoscopic disease activity is minimal [18]. As mentioned above, there are other features that can further increase the risk of dysplasia and cancer in patients with UC, in addition to disease extent, activity or duration. PSC is a well-established risk factor. Jess et al. found that UC patients with PSC compared with patients without PSC were at significantly increased risk of developing CRC (RR: 9.13; 95% CI: 4.52–18.5) [10]. Another population-based study determining the prevalence of PSC among patients with UC requiring proctocolectomy was higher than the general UC population [20]. Family history of previous CRC is also a well-defined risk factor for UC patients progressing to dysplasia. As a result, multiple guidelines suggest that those UC patients with a first-degree relative diagnosed with CRC before 50 years of age be classified as high risk, and therefore should receive annual colonoscopy, as is the recommendation for those with PSC [21–23]. CRC risk in CD
Wide variations have been reported for the risk of CRC in patients with CD compared with those with UC [24–27]. Nonetheless, most studies show that colonic CD patients are likely at an increased risk for CRC compared with age-matched average risk populations [28]. One meta-analysis reported a 2.5-fold (95% CI: 1.3–4.7) increased RR in patients with colonic CD, compared with those with isolated ileal disease only (1.1 [95% CI: 0.8–1.5]) [29]. More data are needed to better characterize 848
dysplasia risk in Crohn’s colitis; however, the signals to date suggest these patients should be approached similarly to those with UC [7,9]. Changes in magnitude of risk
Early population-based studies demonstrated an increased risk of malignancy with IBD, specifically UC [13,28,30–33]. Follow-up studies from these early reports have reaffirmed an elevated risk of CRC in IBD, however, the magnitude of risk may not be as high as initially thought. Rates from these studies may have been artificially elevated for several reasons, including the use of data from referral centers, the inclusion of case reports and differences in inclusion and exclusion criteria. A recent metaanalysis demonstrated a pooled standardized incidence ratio of CRC in IBD patients of only 1.7 (95% CI: 1.2–2.2) [34]. A smaller cohort study from Copenhagen determined that the risk of developing CRC in patients with IBD over 19 years was not elevated. The authors speculated this finding was due to active surveillance programs, early colectomy as well as the use of 5-aminosalicyic acid (ASA) for treatment relapse, a topic that remains controversial [35]. Lutgens et al. suggested the decreased magnitude of risk is an artifact of an aging cohort [34] and suspected that reanalysis of older cohort studies are limited, since only a few new IBD patients have been added to the initial cohort, which have already had the highest-risk patients develop CRC. This results in a marginal change to the number of people at risk and therefore a lower risk ratio. It is also possible that medical and surgical interventions, such as improved surveillance, increased colectomy rates and better medical management have caused a true decline in CRC rates in IBD [36–39]. For example, a Swedish cohort study found that risk of dying from CRC for patients with IBD has decreased significantly over the past 35 years [40]. Other studies have found similar results, suggesting a decline in CRC rates in patients diagnosed with IBD [9,10,34]. The contribution of medical therapy on this observed decline in risk is interesting, but remains unclear. One meta-analysis, which analyzed nine studies, displayed a protective association with the use of 5-ASA and CRC risk (OR: 0.51; 95% CI: 0.37–0.69), the theory being decreased inflammation is protective [41]. However, a more recent meta-analysis evaluating the chemoprotective characteristics of 5-ASA therapy did not show any significant benefit [42]. Among patients with PSC and UC, data from a randomized controlled study and a cross-sectional study demonstrated a reduced risk of dysplasia with use of ursodeoxycholic acid, suggesting a cytologic protective role for this bile acid [43,44]. Furthermore, treatment modalities have changed significantly since early publications of CRC risk estimates and the impact of immunomodulators such as azathioprine, methotrexate and biologic therapy with anti-TNFs on observed declines in dysplasia need to be further elucidated [45]. Detecting dysplasia
Detecting dysplasia in the colon is the principal goal of IBD surveillance programs. One of the major challenges of dysplasia Expert Rev. Anticancer Ther. 14(7), (2014)
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CRC in IBD
surveillance is that while dysplasia may occur in endoscopically visible mucosal abnormalities (e.g., polyps, nodules or masses), referred to as dysplasia-associated lesions or masses (DALMs), it can also occur in relatively flat lesions that may not be appreciated at the time of colonoscopy and detected only in random biopsies. This lesion has been referred to as ‘flat dysplasia’. With the improvements in the quality of endoscopic images and development of new surveillance tools (discussed below), endoscopists have now been able to become even more descriptive in the description of the morphology of these lesions. This has culminated in the development of the Paris classification of neoplastic lesions, which should be used routinely in reporting [46]. A classification system for dysplasia was developed by a collaborative group of pathologists in 1983, which subdivided dysplasia as negative, indefinite or positive [47]. The Vienna Classification has more recently been developed to better characterize dysplasia and provide clinical relevance to the histologic findings [48]. Using this system, dysplasia is further subclassified as either indefinite for dysplasia/neoplasia, low-grade dysplasia/ neoplasia, high-grade dysplasia/neoplasia or invasive neoplasia. Detecting dysplasia is important as not only does the dysplastic focus detected have the potential to evolve into or may already harbor adenocarcinoma, but it may also be an indicator of dysplasia or adenocarcinoma elsewhere in the colon. Colectomy specimens of patients with UC who have low- and high-grade dysplasia have been associated with an increased likelihood of adenocarcinoma. Patients with high-grade dysplasia have been shown to have a synchronous colon cancer at the time of colectomy in 40–50% of cases [7,9]. The association of low-grade dysplasia with co-existing or progression to adenocarcinoma is less clear and has ranged in the literature from 10 to 50% of cases [49,50]. One retrospective study of pathology reports found endoscopic evidence of low-grade dysplasia has positive predictive value of 70% for finding a synchronous cancer [51]. The association between dysplasia and CRC risk is likely similar in CD [29,52]. Indefinite neoplasia/dysplasia, as discussed above, is often noted when surveillance is performed at the time of disease activity, which creates challenges in differentiating changes typical of reactive epithelium and dysplasia. As in the general population, patients with IBD can also develop sporadic adenomas. These can often create a challenge in management as it is occasionally difficult to differentiate disease-associated dysplasia, as described above, and sporadic dysplasia in an adenoma that may have evolved independent of the underlying IBD. This distinction is usually made based on the appearance of the lesion at colonoscopy. Penduculated or sessile polyps are more likely to be typical of sporadic adenomas commonly seen in non-IBD patients and are therefore referred to as ‘adenoma-like DALMs’. Ulcerated, flat or plaque-like lesions are often considered more irregular and less likely to be that of a typical sporadic adenoma and have therefore been termed ‘non-adenoma-like DALMs’ [37,53]. The former are often managed according to general CRC screening guidelines and removed endoscopically, whereas diseaseassociated dysplasia warrants colectomy, closer surveillance or informahealthcare.com
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endoscopic mucosal resection. A multidisciplinary approach involving the endoscopist, pathologist and patient is needed in making a therapeutic plan with consideration of clinical factors including disease duration, distribution, PSC or a family history of CRC [54,55]. It is evident that the current histologic and endosopic classification systems do have some shortcomings. Much of these systems are subjective and therefore susceptible to interobserver variability, a finding that has been confirmed in several studies in the literature [56,57]. The difference between high- and low-grade dysplasia can significantly impact the treatment plan and therefore should be reviewed and confirmed by an expert [58]. For example, patients with low-grade dysplasia often require a careful review with a multidisciplinary team to decide whether or not to proceed with surgery [59]. It is therefore imperative that pathologists with extensive experience scrutinize biopsies so that patients and physicians are able to make the most informed decisions. Managing dysplasia
The optimal surveillance methods for CRC in patients with IBD remain unclear. Several confounding factors and a lack of randomized controlled trials contribute to the inability to determine the best methods of detecting CRC and its precursors among IBD patients. A Cochrane review determined that there was no clear evidence that surveillance colonoscopy increased survival. In their pooled analysis, 7% of patients in the surveillance group compared with 11% of patients in the non-surveillance group died from CRC, respectively (RR: 0.81; 95% CI: 0.17–3.83) [60]. However, this review also demonstrated indirect evidence that surveillance reduces the risk of death from CRC in patients with IBD by detecting cancer earlier. Furthermore, data from case– control studies, retrospective studies and meta-analyses have led to consensus guidelines for surveillance, and despite the weak evidence in support of colonoscopy surveillance, most endoscopists do subscribe to this practice. The goal of surveillance is to detect dysplasia so that appropriate stratification can be made to determine subsequent treatment steps. It is generally accepted that patients with flat high-grade dysplasia should undergo colectomy because of the high rates of progression to or coexisting CRC [21,22,61]. Those patients with multifocal flat dysplasia should also be considered for proctocolectomy [62–64]. Low-grade unifocal dysplasia remains more controversial. Weinstein et al. suggested that given the inherent error in surveillance techniques and the significance of being diagnosed with CRC, all patients with dysplasia (including unifocal low-grade dysplasia) who are willing and able should undergo colectomy [7]. However, the unclear magnitude of risk of progression of low-grade dysplasia as mentioned above as well the fact that dysplasia can be overcalled during times of disease activity warrants careful consideration and a multidisciplinary review prior to finalizing a management plan [58]. Conversations with patients should include the discussion of risks and benefits of surgery versus that of ongoing surveillance, which may fail to detect occult malignancy. One medical decision analysis for patients with unifocal flat 849
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Gallinger & Weizman
low-grade dysplasia suggested a benefit in quality of life and lower costs among patients who chose immediate proctocolectomy over intensive surveillance [49]. If a DALM is seen on initial surveillance colonoscopy, multiple biopsies should be taken throughout the entire colon. Current guidelines suggest that all IBD patients with non-adenoma DALMs should undergo colectomy [65]. As mentioned previously, patients with adenoma-like DALMs need a thorough clinical review when determining whether to proceed with colectomy. Evidence exists that these patients can be managed successfully with complete polypectomy and continued surveillance, much like the general population [53]. A unique situation is in UC patients with colonic strictures, as these are considered a high risk of developing CRC and colectomy is often indicated. If biopsies of a stricture show no evidence of dysplasia and a decision is made to continue with ongoing surveillance, very close and cautions monitoring is required [55]. Major organization surveillance guidelines
Multiple organizations have created specific guidelines for CRC surveillance in patients with IBD. TABLE 1 summarizes the recommendations from the American Gastroenterology Association [18,65], the American Society for Gastrointestinal Endoscopy [64,66], the British Society of Gastroenterology [21,61], the American College of Gastroenterology [62,63] and more recently the European Crohn’s and Colitis Organization [22]. These new guidelines expand on some of the discordant recommendations of previous guidelines. In addition, recommendations about the use of chromoendoscopy (CE) are discussed. Surveillance programs for CD often mimic those that have used data from UC patients. Expert commentary
Dysplasia surveillance is a critical component of providing high-quality care to patients with IBD. While the evidence in support of its impact on decreasing mortality from CRC is unclear, most providers have routinely incorporated it into practice [67]. These patients have been consistently shown to be at increased risk of CRC compared with the general population, and most physicians see death from CRC in patients with IBD as an unacceptable outcome. However, the magnitude of risk of CRC in this population may be changing, likely due to both changing methodologies in evaluating IBD cohorts as well as improved medical therapy, widespread dissemination of dysplasia surveillance guidelines and earlier referral for colectomy. Our IBD patients have been shown to be insufficiently informed regarding long-term risk of disease, including CRC risk, and in order to provide high-quality, patient-centered care, more clarity on the true magnitude of risk and best methods to potentially reduce this risk is needed [68]. Although major organizations have developed IBD/CRC surveillance guidelines, and while the core suggestions remain similar, incongruence has left physicians uncertain [69]. A proactive effort in increasing future study that may provide more data on the actual CRC risk in IBD and the impact of surveillance in 850
augmenting this risk is essential. Moreover, the impact of newer technologies that may replace random colonic segment biopsies holds promise for improving efficiencies and possibly cost of surveillance and warrants close evaluation. Five-year view
The past few decades have witnessed the introduction of new equipment and techniques designed to enhance the detection of dysplasia on endoscopy. Of note, among the most widely studied imaging techniques, CE may provide a higher diagnostic yield of detecting dysplasia. CE allows the endoscopist to apply stains such as methylene blue or cresyl violet or contrast agents such as indigo carmine to the mucosa, with the goal of identifying areas of flat dysplasia or mucosal abnormalities that would be otherwise missed with conventional, white-light colonoscopy. Randomized controlled trials have shown that CE is superior to standard white-light endoscopy techniques [70,71]. A meta-analysis by Subramanian et al. found an increase in detection of dysplasia with CE compared with white light of 7% (95% CI: 3.2–11.3), with a number needed to treat of 14.3 [72]. Using the Kudo pit system, gastroenterologists were able to increase their detection of dysplastic mucosa and subsequently reduce the number of biopsies for adequate surveillance [73]. The success of CE has resulted in an increasing number of gastroenterologists incorporating this technique into their practice, leading some to advocate its incorporation [74] into routine surveillance programs [22,61,64]. However, the need for more evidence in support, the relatively longer time and training required to perform the procedure and the requirement of excellent bowel preparation has limited its widespread use. Narrow band imaging (NBI) is another novel technique that allows increased resolution of mucosa without dyes. It has been evaluated for IBD surveillance programs. Controversy exists whether NBI should be routinely used in surveillance programs, as some studies demonstrate increased miss rates with NBI compared with CE [75,76]. Other studies revealed equivalence between NBI and CE in detecting dysplasia (18.5 vs 16.7%, respectively; p = 0.068) [77]. One meta-analysis of eight studies found that NBI with magnification had a high diagnostic accuracy for characterizing high-grade dysplasia, potentially improving the yield of targeted biopsies [78]. Similarly, a metaanalysis by Wu et al. of 11 studies demonstrated NBI has high diagnostic precision for detecting colorectal neoplasia [79]. Continued randomized controlled trials of these new imaging techniques will allow major organizations to determine their role in surveillance programs. Other new techniques being explored include virtual CE, confocal laser endomicroscopy (CFE), autofluorescence imaging and endocytoscopy. When combined with CE, CFE allows the viewer to see live in vivo histopathology, with 1000-fold magnification of the tissue [80]. CFE is becoming a well-established option for the early detection of dysplasia, with one study showing a 4.75-times increased neoplasia detection rate (p = 0.005) with CFE and CE together compared with CE Expert Rev. Anticancer Ther. 14(7), (2014)
informahealthcare.com
Colectomy with flat dysplasia
Need assessment with patient
High grade
Low grade
Colectomy with flat, multifocal dysplasia Unifocal – need individualized risk assessment with patient
Colectomy with flat, multifocal dysplasia
Urgent repeat chromoendoscopy to assess for associated endoscopically visible lesions to resect, and if not then colectomy Multidisciplinary, detailed team discussion with patient to decide if to proceed with a colectomy OR potential for chromoendoscopic colonoscopy with additional random biopsies within 3 months Need individualized risk assessment with patient Colectomy should be considered with flat dysplasia
If polypectomy is complete by histology, and biopsies from flat mucosa adjacent show no dysplasia and there are no other areas of dysplasia, close follow up with chromoendoscopy at 3 months and then annual surveillance is recommended Colectomy with flat dysplasia
Colectomy
Pan-colonic methylene blue or indigo carmine chromoendoscopy with targeted biopsies of visible lesion If chromoendoscopy not available, random biopsies (4 every 10 cm) should be performed, however, this is inferior to detecting neoplastic lesions
Same as average risk
8–10 years
8–10 years
ECCO
Colectomy with flat dysplasia
Colectomy
Pancolonic dye spraying If no chromoendoscopy used, 2–4 samples every 10 cm of entire colon and extra for suspicious areas
Multiple biopsies
Four quadrants every 10 cm from cecum to rectum for 32 total Suspicious lesions
Colectomy
Not mentioned
15–20 years
8–10 years
BSG
8–10 years
8–10 years
8–10 years
ACG
Same as average risk
15 years
8–10 years
ASGE
‡
For ECCO guidelines, all visible lesions with dysplasia should be completely resected by an experienced endoscopist, irrespective of location and grade. Definition of risk as per BSG guidelines – High risk: Extensive with moderate/severe active endoscopic/histological inflammation or stricture in past 5 years or dysplasia in past 5 years and declining surgery or primary sclerosing cholangitis or family history of colorectal cancer at age less than 50 years; Intermediate risk: Extensive colitis with mild active endoscopic/histological inflammation or post-inflammatory polyps or family history of colorectal cancer diagnosed at age
