Jianlin Xie, Steven H Itzkowitz, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York City, NY 10029, United States
Correspondence to: Steven H Itzkowitz, MD, GI Division, Box 1069, Mount Sinai School of Medicine, One Gustave Levy Place, New York City, NY 10029, United States. email@example.com
Telephone: +1-212-6599697 Fax: +1-212-8492574
Received: May 16, 2007 Revised: June 11, 2007
Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeoxycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohns disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal-anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.
© 2008 WJG. All rights reserved.
Key words: Colon cancer; Inflammatory bowel disease; Dysplasia; Chemoprevention; Colonoscopy; Genomic instability
Xie J, Itzkowitz SH. Cancer in inflammatory bowel disease. World J Gastroenterol 2008; 14(3): 378-389 Available from: URL:http://www.wjgnet.com/1007-9327/14/378.asp DOI: http://dx.doi.org/10.3748/wjg.14.378
The two forms of inflammatory bowel disease (IBD), Crohns disease (CD) and ulcerative colitis (UC), are characterized by chronic, relapsing inflammation of the intestines. First described in a report by Crohn and Rosenberg in 1925, colorectal cancer (CRC) in patients with IBD has long been recognized. Even years after their disease is controlled with medications, IBD patients still live with the fear of developing cancer. CRC is the most common site of cancer in IBD, although cancer in other organs can occur. Together with the hereditary syndromes of familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, IBD is among the top three high-risk conditions for CRC. To date, our understanding of CRC pathobiology has come from studies of patients with UC more so than Crohns colitis. This review will focus mainly on the problem of CRC, and then address other cancers such as small intestinal adenocarcinoma, cholangiocarcinoma, and hematologic malignancies.
COLORECTAL CANCER in Patients with IBD
Prevalence and Incidence of CRC
The exact magnitude of the risk of cancer has been difficult to quantify due to various biases and methodological errors in published studies. Early estimates of CRC complicating UC were based on crude percentages and all were from major medical institutions, predominantly tertiary referral centers. Studies from these centers often included a greater proportion of patients who had more severe disease and cancer had already complicated their colitis. These center-based studies often overestimate the risk. Later population-based studies tended to include more patients with limited disease or those who have undergone colectomy and may thereby underestimate the true risk. Based on a 2001 meta-analysis by Eaden et al, including 116 studies from around the world, the prevalence of CRC in patients with UC is approximately 3.7% overall and 5.4% for those with pancolitis. In comparison, CRC in Crohns disease has been less well studied. Early studies showed no statistically significant increase in cancer risk among the Crohns disease patients. However, the lack of the risk of cancer in these studies was often due to inclusion of all patients with Crohns disease and failed to correct for the small subsets of those with extensive, longstanding and unresected colonic disease. Hence, when patients with longstanding, anatomically substantial Crohns colitis are considered, the risk of CRC is similar between Crohns colitis and UC. Indeed, a population-based study from Manitoba, Canada found that the risk for colon cancer among patients with both UC and Crohns colitis is approximately 2-3 fold greater than the general population and that the risk of rectal cancer is increased 2-fold in UC but not Crohns colitis.
Clinical features of colitis-associated CRC
Compared with sporadic colorectal carcinoma (SCC), CRC arising in patients with IBD has several distinguishing clinical features. Colitis-associated colorectal cancer (CAC) affects individuals at a younger age than the general population. CAC progresses to invasive adenocarcinoma from flat and nonpolypoid dysplasia more frequently than SCC. CACs more often have a higher proportion of mucinous and signet ring cell histology. There is background of chronic inflammation in colitis and a higher rate of two or more synchronous primary CRCs. The multifocality of CAC relates to the broader field effect of mucosal inflammation that gives rise to the neoplasia. In some studies, patients were found to have cancer more proximal in the colon. Finally, the sequence of molecular events leading from dysplasia to invasive adenocarcinoma is different from that of SCC (discussed below).
Molecular features of sporadic colon cancer
To place the molecular pathogenesis of colitis-associated neoplasia in proper perspective, it is important to appreciate the molecular events involved in the development of SCC. SCC arises as a result of genomic instability. The two main types of genomic instability that contribute to colon carcinogenesis are chromosomal instability (CIN) and microsatellite instability (MSI), accounting for 85% and 15% of SCC, respectively. Chromosomal instability results in abnormal segregation of chromosomes and abnormal DNA content (aneuploidy). As a result, loss of chromosomal material (loss of heterozygosity) often occurs, such as APC and p53. These genes can also be rendered nonfunctional by mutation.
Loss of APC function is typically an early event in SCC pathogenesis. The APC gene thus has been considered the gatekeeper of the colon (Figure 1). Some 85% of all sporadic and inherited colorectal tumors show loss of APC function, usually through protein truncation or allelic loss. The APC gene is located on chromosome 5q21-q22. The key tumor suppressor function of the APC protein lies in its ability to destabilize free b-catenin. Among the 15% of colon carcinomas that retain wild-type APC, point mutations have been found in b-catenin that change one of the four serine/threonine residues in the N-terminus, the putative targets of glycogen synthase kinase-3b (GSK-3b). These mutations thus render b-catenin refractory to phosphorylation by GSK-3b, increasing free b-catenin levels. Accumulation of stabilized free b-catenin is an early event and perhaps the initiating event in intestinal tumorigenesis. Inactivation of both APC alleles is found in a majority of small colorectal adenomas in humans and in the smallest detectable tumors in mice heterozygous for an inactivating mutation in APC. Furthermore, intestine-specific expression of a dominant-negative form of b-catenin, which lacks the putative GSK-3b targets sites, leads to the development of adenomas. How the loss of APC or stabilization of b-catenin leads to development of cancer is not yet fully understood. Once a sporadic adenoma forms, other changes in genetic regulation occur, such as induction of k-ras oncogene and loss of function of tumor suppressor genes on chromosome 18q in the region of the deletion in colon cancer (DCC) and in pancreatic cancer (DPC4) genes. Loss of p53 gene function occurs late and is believed to be the defining event that drives the adenoma to carcinoma.
Tumors that arise via the CIN/tumor suppressor gene pathway are typically microsatellite stable (MSS). The remaining 15% of sporadic CRCs arise through the MSI pathway. The MSI pathway involves the primary loss of function of genes that usually repair DNA base-pair mismatches that occur during the normal process of DNA replication in dividing cells. In humans, at least six different proteins (hMSH2, hMLH1, hPMS1, hPMS2, hMSH6, and hMLH3) comprise the mismatch repair system. These proteins form specific heterodimers to coordinate DNA repair and the recruitment of other proteins, such as polymerases and helicases, necessary for mismatch repair. Germline mutations of DNA mismatch repair genes, predominantly hMLH1 (33%) and hMSH2 (31%), are responsible for the familial syndrome of heriditary nonpolyposis colon cancer. In addition, approximately 15% of sporadic tumors from the colon, rectum, and other organs demonstrate MSI. Interestingly, the most common mechanism causing MSI in sporadic colon cancers is not genetic mutation, but rather transcriptional silencing of hMLH1 as a consequence of methylation of the hMLH1 promoter.
Epigenetic alterations can also contribute to altered gene expression in colon carcinogenesis. The CpG island methylator phenotype occurs when cytosines in the promoter region of genes become extensively methylated. A number of human cancer genes that contain hypermethylation of promoter CpG islands have been identified. These include hMLH, p16INK4a, and E-cadherin. The process of methylation is an area of intense investigation, and it is anticipated that this line of research should help to define further the molecular pathways involved in CRC in a variety of clinical settings.
Molecular features of CRC in IBD
The neoplastic transformation in IBD is thought to be similar to the adenoma-carcinoma sequence in sporadic CRC (Figure 1). However, unlike SCC, where dysplastic lesions arise in one or two focal areas of the colon, in colitic mucosa, it is not unusual for dysplasia or cancer to be multifocal, reflecting a broader field effect. Many of the molecular alterations responsible for sporadic CRC development also play a role in colitis-associated colon carcinogenesis. The emerging evidence suggests that the two major pathways of CIN and MSI also apply to CACs and with roughly the same frequency (85% CIN, 15% MSI). Distinguishing features of CAC, however, are differences in the timing and frequency of these alterations (Figure 1). For example, APC loss of function, considered to be a very common early event in SCC, is much less frequent and usually occurs late in the colitis-associated dysplasia-carcinoma sequence. Conversely, p53 mutations in sporadic neoplasia usually occur late in the adenoma-carcinoma sequence, whereas in patients with colitis, p53 mutations occur early and are often detected in mucosa that is non-dysplastic or indefinite for dysplasia.
Methylation is assuming increasing importance as a mechanism contributing to the genetic alterations in CAC (Figure 1). Methylation of CpG islands in several genes seems to precede dysplasia and is more widespread throughout the mucosa of UC patients.
CRC risk factors
Several factors have been identified which either increase or decrease CRC risk in the setting of IBD (Table 1). With respect to increasing CRC risk, the most important factor, reproducibly found across many studies, is the duration of colitis. CRC is rarely encountered before 7 years of colitis. The pooled estimate of cumulative CRC incidence in UC in Eadens meta-analysis was 2% at 10 years, 8% at 20 years, and 18% after 30 years of disease. This may overestimate the risk since many studies in the meta-analysis were from the pre-surveillance era. Thus, a recent study by Rutter et al showed lower cumulative incidence of CRC in patients with UC even at the referral-based St. Marks Hospital in London: 2.5% after 20 years of disease, 7.6% after 30 years, and 10.8% after 40 years of follow-up.
Extent of colitis is an independent risk factor for the development of CRC. The more colonic surface that is involved with colitis, the greater the CRC risk. However, different criteria exist regarding classification of the extent of colitis. Most early reports of surveillance programs used barium enema results at diagnosis as the standard for defining disease extent. A population-based study of over 3000 UC patients in Sweden examined by barium enema demonstrated that patients with proctitis had a standardized incidence ratio (SIR) of 1.7 [95% confidence interval (CI) 0.8-3.2] compared with age-matched population controls without UC, whereas those with left-sided colitis had a SIR 2.8 (95% CI 1.6-4.4), and those with pancolitis had SIR 14.8 (95% CI 11.4 to 18.9). Endoscopic and histologic evidence of inflammation are valid alternative criteria particularly in high risk patients. Very few studies have correlated CRC risk with histologic extent of disease, even though microscopic evidence of colitis is arguably a better indicator of disease extent than either endoscopic or radiographic changes. Mathy et al reviewed 30 colectomy specimens and showed that dysplasia and CRC can arise in areas of microscopic colitis that are proximal to areas of gross colitis, suggesting that indeed histologic changes, even without colonoscopic alterations, might better define disease extent for the purposes of cancer risk. Backwash ileitis, defined as pancolitis with superficial involvement of the terminal ileum, has been suggested as an additional increased risk of CRC, but this requires additional confirmation.
IBD patients with a family history of CRC have at least a
two-fold higher risk of CRC[20-22]. Both UC and Crohns
With regard to reducing CRC risk, there are two main choices: removing the colon versus conducting a lifelong program of surveillance (Table 1). Although prophylactic total proctocolectomy after 7-10 years of colitis would prevent most cancers, it would result in many colectomies that were not necessary and a substantially altered quality of life for patients. Thus cancer prevention in this patient population has focused on periodic surveillance colonoscopies. Surveillance should be viewed as a program that includes regular visits to the doctor, the use of medications to control inflammation (some of which may have chemopreventive effects, see below), and regular colonoscopies. The goal of surveillance colonoscopy is to detect neoplastic lesions before they become biologically dangerous. Thus, the detection and interpretation of dysplasia is crucial to successful surveillance.
Macroscopic classification of dysplasia
By definition, dysplasia is unequivocal neoplasia. Despite considerable heterogeneity in appearance, dysplasia in IBD is often classified macroscopically as raised or flat, depending on whether it corresponds to an endoscopically visible lesion. Raised lesions, conventionally referred to by the term DALM (dysplasia associated lesion or mass), can appear as polyps, bumps, plaques and velvety patches[31,32]. Such lesions can blend easily with the gross inflammatory abnormalities commonly encountered in colons with IBD, making their endoscopic detection difficult even for experienced practitioners.
Unlike sporadic cancers arising from polypoid lesions, IBD-associated cancers can arise from flat dysplastic lesions. Flat dysplasia is detected microscopically in random biopsies from unremarkable mucosa. Its detection therefore depends on adequate sampling of the mucosa by the endoscopist, or more recently, by chromoendoscopy methods which highlight suspicious lesions and permit targeted biopsies (see below). If random biopsies are performed without dye spray enhancement, it has been estimated that to exclude dysplasia with a 90% certainty, 33 biopsy specimens are required, and to increase the accuracy to 95%, nearly twice the number of biopsy specimens are required. Current surveillance strategies recommend annual colonoscopy with multiple biopsy specimens (4 circumferential) taken from every 10 cm of diseased colon, with additional biopsy specimens at sites of strictures or raised lesions. However, questionnaire surveys have suggested that the number of biopsies taken by endoscopists in routine practice often falls short of recommended guidelines[35,36].
The significance of dysplasia in endoscopically visible lesions came from studies that reported high rates of cancer when patients with such lesions underwent colectomy[31,32]. Blackstone et al reported cancers in 7 of 12 DALM-bearing colons, including 5 with only mild or moderate dysplasia in the preoperative biopsies. A subsequent compilation of published results from ten surveillance programs reported cancers in 17 of 40 (43%) colectomies performed because of a DALM. It was concluded that DALM is an indication for colectomy irrespective of the grade of dysplasia in preoperative biopsies. While not fully appreciated at the time, the original studies of DALMs dealt exclusively with lesions that could not be removed endoscopically for microscopic examination. Thus, the significance of such lesions as an indication for surgery is similar to that of endoscopically non-resectable sporadic adenomatous polyps, which frequently harbor invasive cancer at the polyp base despite the presence of low-grade dysplasia in their more biopsy-accessible upper portions.
More recently, we have come to realize that not all types of polypoid dysplasia in patients with IBD carry the same significance. Some polyps may be adenomatous polyps unrelated to colitis and can be managed by endoscopic polypectomy like polyps in the general population[38-40]. One example is the dysplastic polyp encountered in a bowel segment that is entirely free of disease (e.g., in the proximal colon of a patient with left-sided ulcerative colitis). In such cases, one would take the precaution to biopsy the mucosa surrounding the polyp to assure the absence of microscopic disease. Similarly, a dysplastic polyp with a well-defined stalk can be regarded as a sporadic adenoma, even when encountered in a colitic region, if the mucosa lining its stalk is non-dysplastic.
Conservative management is also reasonable for dysplastic polyps that are adenoma-like[41,42]. These polyps are endoscopically indistinguishable from sporadic sessile adenomatous polyps, i.e., discrete and ovoid or round, are completely resectable by the endoscope, and are not surrounded by flat dysplasia. Such lesions have long posed a dilemma for endoscopists who were familiar with the DALM concept but reluctant to advocate colectomy for what appeared to be innocuous lesions and possibly nothing more than fortuitous adenomas. Histology has not provided a reliable means of making this distinction in individual cases, since the histological features of dysplasia in the setting of IBD and in true adenomas can be virtually identical. A 1999 study from The Mount Sinai Hospital in New York reported that conservative management of a cohort of 48 UC patients with a total of 70 such polyps, including 3 with high-grade dysplasia, resulted in no adverse outcomes during a mean follow-up period of 4.1 years. Similar conclusions were reached in a concurrent study from Brigham and Womens Hospital that was confirmed upon longer follow-up. As a result, the burden of deciding whether a polyp qualifies as adenoma-like rests with the endoscopist. Molecular markers may ultimately afford a more objective means of making these distinctions[45,46], but to date, these analyses are not applicable to routine clinical practice.
Microscopic classification of dysplasia
Gastrointestinal dysplasia is defined microscopically as replacement of the native intestinal epithelium by an unequivocally neoplastic, but noninvasive, epithelium. It is synonymous with the term intraepithelial neoplasia used in other organ systems. A standardized classification system of dysplasia in IBD was established and divided dysplasia into five categories: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia (LGD), high-grade dysplasia (HGD) or invasive cancer. A further subdivision of the indefinite category includes probably negative, probably positive, unknown, however many pathologists regard this as optional.
The cellular abnormalities that define dysplasia in IBD are analogous to those characterizing neoplastic tissue in general, namely nuclear abnormalities reflecting inappropriate cellular proliferation and cytoplasmic abnormalities reflecting clonality and aberrant differentiation. The distinction between low- and high-grade dysplasia depends upon the distribution of nuclei within the cells, low-grade dysplasia being characterized by nuclei that remain confined to the basal half of the cells and high-grade by nuclei that are stratified haphazardly between the basal and apical halves. Not surprisingly, pathologists are frequently confronted with biopsies that lie in a gray zone between the two categories, and some degree of subjectivity is therefore unavoidable. The diagnostic category indefinite for dysplasia is an acknowledgement of the difficulty pathologists face in discriminating between dysplasia and reactive epithelial changes, although experienced pathologists are usually able to discriminate between the two.
There is inconsistency among pathologists in the diagnosis of dysplasia on biopsy. In one study, there was only 60% agreement for a diagnosis of LGD. Similarly Lim et al found that the kappa coefficient for interobsever agreement between ten pairings of five specialist gastrointestinal (GI) pathologists ranged from 0.06 to 0.39. Other studies comparing diagnoses of dysplasia among different pathologists, both prospectively and retrospectively, have concluded that levels of interobserver agreement are fair at best even among specialists in gastrointestinal pathology[50-54]. The best agreement levels tend to occur at the two extremes of negative and high-grade dysplasia and the poorest levels in the two gray zones between low-grade and high-grade dysplasia and on either side of indefinite for dysplasia. From a practical standpoint, it has been recommended that diagnoses carrying serious management implications be reviewed by at least one additional pathologist with expertise in this area.
BIOLOGY OF DYSPLASIA
Natural history of dysplasia
The natural history of dysplasia is a key factor contributing to the outcome and success of surveillance. The model shown in Figure 1 suggests that colitic mucosa progresses in a systematic fashion: no dysplasia, indefinite dysplasia, LGD, HGD, and finally invasive cancer. Although this is a useful paradigm that facilitates the study of cancer risk markers in IBD, it remains unclear whether dysplasia of one grade may progress (or regress) to another grade. For example, patients undergoing regular colonoscopic surveillance have developed CRC without any prior dysplasia, and it is not necessary for LGD to progress to HGD before cancer arises in the colon[30,56]. This highlights the need to develop markers that are complementary to dysplasia for predicting CRC risk in IBD patients-a subject of ongoing investigation.
In the meantime, we currently rely upon the histological identification of dysplasia to make management decisions. Refinements in interpreting dysplasia based on the 1983 standardized histological criteria have enabled a more accurate prediction of which patients are more likely to progress to advanced neoplasia by excluding those whose biopsies only show reactive changes secondary to inflammation. This was amply illustrated by the St. Marks group who found that the 5-year cumulative rate of progression from LGD to HGD or cancer rose from 16% to 54% once biopsies were more precisely reclassified[53,57].
Dysplasia (of any grade) is associated with a risk of concurrent CRC in IBD. An early study reported 12 cases, described as unresectable single polypoid masses, collections of polyps, or plaque-like lesions, 7 were found to have adenocarcinoma upon colectomies despite multiple biopsies that had not detected it. In a review of ten prospective surveillance trials, 43% of patients who underwent colectomy because of DALM had coexistent CRC, 42% (10 of 24) patients with HGD, and 16% (3 of 19) patients with LGD who underwent immediate colectomy had synchronous CRC. Ullman and colleagues at The New York Mount Sinai Hospital performed a retrospective cohort analysis of 46 patients with UC who had flat LGD but did not undergo immediate colectomy. They found that 27% (3 of 11) patients who underwent colectomy within 6 months of the initial detection of flat LGD had a surprise finding of cancer or HGD. More recently, Rutter et al from the St. Marks Hospital reported 20% of patients with LGD who proceeded to colectomy had concurrent adenocarcinoma and 39.1% who had follow-up of the LGD progressed to subsequent HGD or CRC.
Assuming that early colectomy is not performed, what is the subsequent rate of progression? In the case of patients with HGD, 32% were found to have CRC after some follow-up period. For those with LGD, the probability of eventually progressing to HGD or CRC was 16%-29%. Data from St. Marks Hospital indicate that the 5-year cumulative probability of progressing from LGD to HGD or cancer is 54%. Strikingly similar results were obtained from The Mount Sinai Hospital, with a 5-year progression rate of 53% among 46 patients with initial flat LGD. A recent follow-up analysis from the St. Marks group indicates slightly lower, but still substantial rates of progression. Likewise, a series of 18 patients with LGD followed at the Mayo Clinic demonstrated a 33% 5-year progression rate. Despite these rather similar results from three different patient populations, some authors have reported a substantially lower rate of progression. Befrits et al followed 60 patients with flat LGD from the Karolinska Institute in Sweden and found that none developed cancer and only 2 cases of progression to HGD in DALMs over a mean follow-up period of 10 years. In the series by Lim et al from Leeds in the U.K., they reported that only 3/29 (10%) patients with LGD progressed to HGD or cancer after 10 years. It is worth noting that in the latter two studies, the designation of LGD included specimens that were interpreted prior to the 1983 consensus guidelines, so they might have included cases with indefinite dysplasia.
Because of uncertainty of flat LGD[56,60], these studies have failed to achieve consensus on proper management of flat LGD. Hence, competing options should be discussed with each patient. A patient confirmed to have multifocal flat LGD (2 or more biopsies with LGD from a single screening or surveillance examination) or repetitive flat LGD (2 or more examinations with at least a single focus of LGD), should be strongly encouraged to undergo prophylactic total proctocolectomy. Furthermore, even for patients with confirmed unifocal LGD (only 1 biopsy positive for LGD in a screening or surveillance examination) should also be offered the option of undergoing prophylactic proctocolectomy, since evidence indicates that a 5-year rate of progression to HGD or CRC in this patient group seems to be similar to that of multifocal LGD.
THE MANAGEMENT OF DYSPLASIA
Once a decision is made to place a patient under surveillance, it is recommended that the patient formally agree to enter such a program and is willing to comply. Patients must be made to understand the limitations of surveillance and accept the concept that despite their own cooperation, dysplasia and cancer can still arise even in the hands of skilled endoscopists and pathologists.
The best proof that surveillance colonoscopy effectively reduces CRC mortality would be a prospective, randomized, controlled trial in which patients with longstanding IBD would undergo colonoscopic surveillance whereas controls matched for a similar risk profile would not. However, due to ethical, financial and practical limitations, this type of study will likely never come to pass. We must therefore rely on retrospective studies for insights as to the efficacy of surveillance colonoscopy. In a retrospective study by Choi et al, patients with chronic UC who developed cancer were divided into those who had surveillance colonoscopy and those who did not. Patients undergoing surveillance colonoscopy were found to have less advanced Dukes stage CRC than those who did not and correspondingly had an improved 5-year survival rate (77.2% vs 36.3%, P = 0.026). However, the best evidence that colonoscopy reduces mortality from CRC in UC comes from case-control studies. In one such study, Karlen and colleagues identified 2 of 40 patients with UC and 18 of 102 controls who had undergone at least one surveillance colonoscopy who died as a result of CRC (RR = 0.29), CRC mortality was reduced by as much as 78%, although this did not reach statistical significance. Another study found a similar degree of protection. In these studies, a protective effect was found for individuals who had even one or two surveillance exams. There is also good evidence from prospective, albeit uncontrolled, studies of surveillance colonoscopy that in general, patients who comply with surveillance have cancers detected at earlier stages compared to those who do not comply[53,63]. Of course, cancers will still arise even within a surveillance program, but in balance, the practice of surveillance is beneficial.
Although the gastroenterology community has put its faith in surveillance colonoscopy to prevent CRC in IBD patients, surveillance has its limitations. Previous studies have shown low rates of observer agreement for the histopathologic interpretation of biopsy specimens between general pathologists and GI pathologists, or even among expert GI pathologists[47,48]. Endoscopists fail to take a sufficient number of biopsies to exclude the presence of dysplasia or cancer. Unlike the dysplastic sporadic adenoma which typically assumes a discrete, polypoid shape surrounded by normal mucosa, dysplasia in the colitic colon can be flat or polypoid and is often difficult to discern. This may be particularly troublesome in a colon that is replete with inflammatory pseudopolyps. Furthermore, there is poor understanding of dysplasia amongst trained gastroenterologists. A survey of practicing gastroenterologists and senior GI fellows in the U.S. found that only 19% of respondents correctly identified dysplasia as neoplastic change. Patient drop-out or non-compliance with surveillance contributes importantly to CRC mortality in IBD[49,53] and this must be considered when embarking upon, or continuing, a course of surveillance in individual patients.
RECOMMENDED SURVEILLANCE STRATEGY
Despite the limitations of surveillance colonoscopy, dysplasia remains the best marker for managing cancer risk in IBD. After approximately 7-8 years of colitis, patients should undergo an initial surveillance colonoscopy to determine the extent of colitis and check for neoplasia. The entire colon should be examined, with approximately 4 biopsies taken every 10 cm. Some experts suggest taking more biopsies in the distal rectosigmoid (e.g., approximately every 5 cm) since the distribution of neoplasia in UC still shows a distal predominance. Biopsies should be taken from flat mucosa, but if any raised or suspicious lesions are encountered, these should be removed if possible and processed in separate specimen containers (with additional biopsies taken near the base of the polyp). If a patient is experiencing moderate-severe colitis symptoms, one option is to control the inflammation medically prior to performing the examination in order to minimize difficulties with the histological interpretation of dysplasia. However, one should not defer the colonoscopy too long, since many expert pathologists now feel that they can readily interpret dysplasia even in the presence of active inflammation.
Figure 2 depicts a recommended surveillance strategy. If no dysplasia is detected, the examination should be repeated in 1-2 years. This interval derives in part from studies reporting that interval cancers can develop within 2 years after a surveillance examination. If indefinite dysplasia is reported, the nature of the uncertainty should be discussed with the pathologist. If the suspicion of dysplasia is high (i.e., probably positive), repeat biopsy within 3-6 mo or less may be indicated; if low, the interval can be lengthened to every 6-12 mo. If LGD is detected in a discrete polyp that can be readily resected endoscopically and there is no flat dysplasia immediately adjacent to the polyp or elsewhere in the colon, surveillance can be continued, although the frequency of examinations can be temporarily reduced to every 3-6 mo, particularly to re-evaluate the area of polypectomy. Tattoo of the polypectomy site is advised to permit relocalization of the area on subsequent exams. If LGD is detected in flat mucosa (whether unifocal or multifocal), and is confirmed by a second expert GI pathologist, colectomy should be strongly considered. If the patient refuses, repeat surveillance exams should be undertaken within 3-6 mo or less. However, the patient should be advised that a negative subsequent examination is no assurance of safety, and that temporizing until there is histological progression to HGD or cancer as the indication for colectomy is risky. A patient in whom flat HGD or adenocarcinoma is found and confirmed by two expert pathologists should undergo colectomy unless serious co-morbidities dictate otherwise. If HGD is diagnosed in an adenoma-like polyp but it is completely removed without evidence of flat dysplasia in the adjacent mucosa or elsewhere in the colon, continued surveillance can be entertained. As with any set of recommendations, decisions should be individualized according to the situation of the patient. Hopefully, strategies for surveillance will become more refined as more knowledge of the natural history of dysplasia is obtained.
Patients who have only had small intestinal Crohns disease without colonic involvement are not considered to be at high risk for CRC. For patients with Crohns colitis, much less is known. To date, only one practice-based retrospective surveillance study has been reported in patients with Crohns colitis. Of 259 patients with Crohns colitis affecting at least one-third of the colon for at least 8 years, 16% were found to have dysplasia or cancer over a 16 year period in which 663 examinations were performed, and there were no cancer deaths. While we await additional data on the subject, it seems wise to follow a UC-based surveillance strategy for patients with at least 8 years of substantial Crohns colitis. An important question that remains to be clarified is whether patients with dysplasia or cancer in the setting of segmental Crohns colitis can undergo segmental resection of the involved area or should proceed to a more extensive UC-like surgical approach. Another dilemma that is encountered with Crohns colitis is the management of strictures. This occurs more so than with UC. Finding a stricture in a colon of a patient with UC usually means an underlying malignancy, especially if the stricture is causing symptoms, and is located in the proximal colon. However, since most strictures in Crohns colitis are benign, the patient can often be managed conservatively. Surveillance of such patients often requires using a narrower colonoscope or sometimes dilating a stricture to visualize the proximal mucosa. Consideration should be given to adding brush cytology of strictures to regular forceps biopsies, and performing a barium enema to evaluate for colonic wall irregularity.
New endoscopic techniques and molecular screening approaches
Recent publications on chromoendoscopy have demon-strated a greater yield for dye-spray targeted biopsies compared with numerous non-targeted biopsies and thus enhance the endoscopic detection of dysplastic lesions in colitic colons. In a randomized trial by Kiesslich et al, intraepithelial neoplasia was more than three times as likely to be detected using chromoendoscopy compared with surveillance using nontargeted biopsies (32/84 compared with 10/81; P = 0.003). Rutter et al detected no dysplasia in 2904 non-targeted biopsies in 100 patients, but in targeted biopsies, nine dysplastic lesions were detected, seven of which were visible only with dye spraying by using indigo carmine instead of methylene blue. A recent report by Ochsenkuhn et al from Munich, Germany showed a low frequency of colorectal dysplasia in patients with long-standing IBD by fluorescence colonoscopy with 5-aminolevulinic acid.
Other approaches worth mentioning are to examine the biopsy tissue of patients with IBD for molecular alterations. The best tested of these are aneuploidy, mutations in p53 and ras, and glycosylation abnormalities, particularly increased expression of sialyl Tn antigen (sialyl 2,6 N-acetylgalactosamine). Because the DNA shed into stool should theoretically provide a more comprehensive sampling of abnormal cells than random pinch biopsies, stool DNA testing could potentially contribute to the management of patients with long-standing IBD who are at risk for developing CRC.
Despite the relative protection afforded by surveillance colonoscopies in IBD, there are still patients who develop CRC despite seemingly optimal surveillance. This raises the issue of whether chemoprevention in the form of either medications or dietary supplements might help reduce the risk of CRC in IBD.
Aspirin and other NSAIDs markedly reduce the incidence of, and mortality from, sporadic CRC. Since many patients with IBD take NSAIDs in the form of 5-aminosalicylates (5-ASA), investigators have asked whether 5-ASA compounds might also be protective. Although no study to date has been performed in a prospective manner specifically to address this question, the available data suggest that this may be so. If 5-ASA compounds prevent colonic neoplasia by suppressing inflammation, it follows that other anti-inflammatory medications used in IBD patients should also be protective against CRC. Although one study reported that the use of systemic steroids, and even topical steroids resulted in a significant CRC risk reduction, and others confirm this observation, steroids cannot be used long-term for chemoprevention. There appears to be no chemopreventive activity of 6-mercaptopurine or azathioprine.
In the setting of sporadic CRC, low folate intake has been associated with an increased risk for developing colorectal adenomas and carcinomas[75,76]. Patients with chronic IBD are predisposed towards folate deficiency because of inadequate nutritional intake, excessive intestinal losses with active disease, and reduced intestinal absorption from competitive inhibition from sulfasalazine use. Results of two studies suggest a trend towards protection against CRC in folate users, although neither study demonstrated statistical significance[77,78]. Nonetheless, since it is rather safe and inexpensive, folate supplementation should be considered for CRC risk reduction in patients with longstanding IBD.
In animal models of colon carcinogenesis, ursodiol inhibits carcinogenesis-an effect that may be due to the ursodiol reducing the colonic concentration of the secondary bile acid deoxycholic acid. Ursodiol also has anti-oxidant activity. A study of UC patients with PSC demonstrated that ursodiol use was strongly associated with decreased prevalence of colonic dysplasia. This protective effect remained after adjusting for duration of colitis, age at onset of colitis, and sulfasalazine use. In a follow-up to the randomized, placebo-controlled trial by Pardi et al at the Mayo Clinic, 52 patients with chronic PSC and chronic UC (mean 13 years) were followed for a total of 335 person-years. Ursodiol use was associated with a significant protection against the development of dysplasia and cancer (RR = 0.26, P = 0.034). At the present time, however, we do not know whether ursodiol can prevent neoplastic progression in UC patients without PSC.
Recently, there has been interest in the role statins may play as chemopreventive agents in a variety of cancers. In a population-based case-control study of patients who had diagnosis of CRC in northern Israel between 1998-2004, statin therapy was associated with a modest reduction in CRC in the non-IBD population, but a substantial 94% risk reduction in patients with IBD was observed in a subset analysis of a small number of patients. Further studies will need to verify this benefit.
Although a single retrospective cohort study suggests that therapy with 6-mercaptopurine is not chemopreventive (or carcinogenic), there remain insufficient data regarding the chemopreventive role of immunomodulators in order to make recommendations and likewise, whether patients who require immunomodulator therapy should continue their 5-ASA therapies.
Small bowel cancer in IBD
Most cancers of the small bowel in Crohns disease are adenocarcinoma, usually in the terminal ileum or jejunum. The most common clinical presentation of small bowel cancer is intestinal obstruction. Other important symptoms include diarrhea, weight loss, and abdominal fistulae. These symptoms are also found in Crohns disease. Risk factors for developing carcinoma in small bowel segments of involved mucosa in patients with Crohns disease are poorly defined, although case reports document them in strictured mucosa and fistulae[83-85]. Surgery should be considered if the fistulae or stricture cannot be adequately examined, or symptoms substantially worsen. There is some suggestion that 5-ASA compounds might lower the risk of small intestinal adenocarcinoma.
A number of studies have demonstrated an increased risk of developing adenocarcinoma of the small intestine with small intestinal Crohns disease. Although the absolute number of cases of small bowel adenocarcinoma is low, because of the rarity of this cancer in the general population, the risk is approximately 10-12-fold greater than the general population[4,86]. In the Uppsala study, the investigators reported only one observed case compared with 0.3 expected cases, but the confidence interval was wide. In the Copenhagen study, two cases were observed vs 0.04 expected cases, a 50-fold increased occurrence. In the Tel Aviv study, none of the patients developed small cancer. The material was probably far too small to expect any small bowel cancer cases. In Oxford, a 10-fold increased relative risk was observed for cancer of the small intestine. A population-based Swedish study revealed a significantly increased number of cancer of the small intestine (standardized morbidity ratio, 15.64; 95% CI, 4.26-40.06), however, the occurrence of colorectal cancer was not increased. Another population-based Canadian study encompassing the years 1984-1997 demonstrated an increased incidence rate ratio of carcinoma of the small intestine (17.4; 95% CI, 4.16-72.9).
Patients with UC who have undergone total proctocolectomy with ileal pouch anal-anastomosis (IPAA) have a very small risk of dysplasia arising within the ileal mucosa of the pouch itself. The risk is thought to be higher in patients with chronic pouchitis and associated severe villous atrophy, but this has not been shown in all series. Indeed, a study of 160 patients who underwent biopsy a total of 222 times with an average surveillance time of 8.4 years after surgery showed that in 1800 pouch-years of surveillance, only one patient had focal LGD of the pouch. The risk of neoplasia is greater in the anal transitional mucosa between the pouch and the anal canal, particularly if a cuff of rectal mucosa has been left, and if the indication for the IPAA was rectal dysplasia or cancer. While there are currently no guidelines for endoscopic surveillance after an IPAA procedure, in those patients who have chronic pouchitis and severe villous atrophy or whose original indication for IPAA was dysplasia or cancer, a program of periodic endoscopy with biopsies, paying particular attention to any anal transition zone, is reasonable.
Other cancers in patients with IBD
Squamous cell carcinoma of the anus has been reported in
patients with longstanding, complicated perianal Crohns
An increased risk for hepatobiliary cancers in patients with UC has been found in several[4,96-98] but not all studies. For many of these patients, primary sclerosing cholangitis was the predisposing factor.
The risk of hematopoietic cancer in patients with IBD has been a growing concern. Early case series from The Cleveland Clinic and The Mount Sinai Hospital, as well as other centers reported an increase in leukemia in patients with UC. A recent large cohort study from Sweden, which included nearly 50 000 IBD patients concluded this population has a marginally increased risk of hematopoietic cancer, and in UC, lymphoma occurred as expected (SIR 1.0) but myeloid leukemia occurred significantly more often than expected (SIR 1.8). In Crohns disease, there was a borderline significant increased lymphoma risk (SIR 1.3), essentially confined to the first years of follow up. However, population-based studies from Denmark, Sweden and Canada have failed to substantiate any increased risk of leukemia. Likewise, although an increased number of lymphomas have been reported in some case series[99,102], other series and several population-based studies[87,91,97,98] do not support the notion that patients with UC or Crohns disease are at increased risk of lymphoma. However, a population-based study from Canada reported an increased rate of lymphoma among male patients with Crohns disease.
The risk of lymphoma or leukemia in IBD has raised concerns regarding the lymphogenic potential of immunomodulatory therapy. Following the introduction of tumor necrosis factor inhibitors in the treatment of Crohns disease, subsequent reports indicated an excess of malignant lymphoma among treated patients[103,104] and raised fears of an iatrogenic lymphoma risk. However, these reports have also highlighted the lack of robust data on the expected occurrence of malignant lymphomas in TNF naοve (but otherwise treated) patients with IBD[105-107]. Studies examining the risk of lymphoma associated with azathioprine (AZA) and 6-mercaptopurine (6-MP) have yielded variable results. Heterogeneity in the type, dose, and duration of immunomodulatory therapy may be responsible for this discrepancy. A few studies with suboptimal dosing failed to demonstrate an increased risk of lymphoma[4,108-112]. In contrast to these reports, other studies have demonstrated an increased risk of lymphoma after purine analog therapy[113-115]. In one such study, Kandiel et al reported a 4-fold-higher risk of lymphoma inpatients treated with AZA or 6-MP compared with the general population. Another recent study showed a statistically significant increase in the development of malignancies among IBD patients treated with 6-MP who developed sustained leucopenia.
The future looks promising with respect to new developments in the management of cancer risk in IBD. Chromoendoscopy is likely to be used more for management, but whether the predictable increase in the yield of dysplasia will alter the overall natural history remains to be studied. In the modern era of molecular diagnostics, tissue and even stool samples of patients with IBD can be investigated for molecular alterations. For example, University of Washington investigators have demonstrated that because there is often widespread genomic instability throughout the colon of IBD patients, it may be possible to analyze rectal biopsies by DNA fingerprinting or fluorescence in situ hybridization methods to identify patients at particularly high risk. The advent of technology to extract human DNA from stool and look for specific DNA mutations associated with sporadic colon carcinogenesis[117,118] implies that a similar approach may also be worthwhile in IBD patients. It is anticipated that refinements in our knowledge of cancer biology, clinical practice, and molecular discovery will bring a new level of sophistication to the management of patients with longstanding IBD and lower the incidence of CRC in this high-risk population.
1 Crohn BB, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis. Am J Med Sci 1925; 170: 220-228
2 Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001; 48: 526-535 PubMed
3 Sachar DB. Cancer in Crohn's disease: dispelling the myths. Gut 1994; 35: 1507-1508 PubMed
4 Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001; 91: 854-862 PubMed
5 Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87: 159-170 PubMed
6 Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet 2001; 10: 721-733 PubMed
7 Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997; 275: 1787-1790 PubMed
8 Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc Natl Acad Sci USA 1995; 92: 4482- 4486 PubMed
9 Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M, Taketo MM. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 1999; 18: 5931-5942 PubMed
10 Kolodner RD, Marsischky GT. Eukaryotic DNA mismatch repair. Curr Opin Genet Dev 1999; 9: 89-96 PubMed
11 Markowitz S. TGF-beta receptors and DNA repair genes, coupled targets in a pathway of human colon carcinogenesis. Biochim Biophys Acta 2000; 1470: M13-M20 PubMed
12 Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58: 5248-5257 PubMed
13 Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomaki P. Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 2000; 156: 1773-1779
14 Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 2001; 10: 687-692 PubMed
15 Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 2001; 61: 3573-3577 PubMed
16 Rutter MD, Saunders BP, Wilkinson KH, Rumbles S, Schofield G, Kamm MA, Williams CB, Price AB, Talbot IC, Forbes A. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006; 130: 1030-1038 PubMed
17 Ekbom A, Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990; 323: 1228-1233 PubMed
18 Mathy C, Schneider K, Chen YY, Varma M, Terdiman JP, Mahadevan U. Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis. Inflamm Bowel Dis 2003; 9: 351-355 PubMed
19 Heuschen UA, Hinz U, Allemeyer EH, Stern J, Lucas M, Autschbach F, Herfarth C, Heuschen G. Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology 2001; 120: 841-847 PubMed
20 Askling J, Dickman PW, Karlen P, Brostrom O, Lapidus A, Lofberg R, Ekbom A. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 2001; 120: 1356-1362 PubMed
21 Nuako KW, Ahlquist DA, Mahoney DW, Schaid DJ, Siems DM, Lindor NM. Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroenterology 1998; 115: 1079-1083 PubMed
22 Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 2000; 14: 145-153 PubMed
23 Jayaram H, Satsangi J, Chapman RW. Increased colorectal neoplasia in chronic ulcerative colitis complicated by primary sclerosing cholangitis: fact or fiction? Gut 2001; 48: 430-434 PubMed
24 Kornfeld D, Ekbom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut 1997; 41: 522-525 PubMed
25 Shetty K, Rybicki L, Brzezinski A, Carey WD, Lashner BA. The risk for cancer or dysplasia in ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 1999; 94: 1643-1649 PubMed
26 Prior P, Gyde SN, Macartney JC, Thompson H, Waterhouse JA, Allan RN. Cancer morbidity in ulcerative colitis. Gut 1982; 23: 490-497 PubMed
27 Greenstein AJ, Sachar DB, Smith H, Pucillo A, Papatestas AE, Kreel I, Geller SA, Janowitz HD, Aufses AH Jr. Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology 1979; 77: 290-294 PubMed
28 Lennard-Jones JE. Cancer risk in ulcerative colitis: surveillance or surgery. Br J Surg 1985; 72 Suppl: S84-S86
29 Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, Williams C, Price A, Talbot I, Forbes A. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004; 126: 451-459 PubMed
30 Harpaz N, Talbot IC. Colorectal cancer in idiopathic inflammatory bowel disease. Semin Diagn Pathol 1996; 13: 339- 357 PubMed
31 Blackstone MO, Riddell RH, Rogers BH, Levin B. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 1981; 80: 366-374 PubMed
32 Butt JH, Konishi F, Morson BC, Lennard-Jones JE, Ritchie JK. Macroscopic lesions in dysplasia and carcinoma complicating ulcerative colitis. Dig Dis Sci 1983; 28: 18-26 PubMed
33 Rubin CE, Haggitt RC, Burmer GC, Brentnall TA, Stevens AC, Levine DS, Dean PJ, Kimmey M, Perera DR, Rabinovitch PS. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 1992; 103: 1611-1620 PubMed
34 Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 1997; 92: 204-211 PubMed
35 Bernstein CN, Weinstein WM, Levine DS, Shanahan F. Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis. Am J Gastroenterol 1995; 90: 2106-2114 PubMed
36 Eaden JA, Ward BA, Mayberry JF. How gastroenterologists screen for colonic cancer in ulcerative colitis: an analysis of performance. Gastrointest Endosc 2000; 51: 123-128 PubMed
37 Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994; 343: 71-74 PubMed
38 Torres C, Antonioli D, Odze RD. Polypoid dysplasia and adenomas in inflammatory bowel disease: a clinical, pathologic, and follow-up study of 89 polyps from 59 patients. Am J Surg Pathol 1998; 22: 275-284 PubMed
39 Rozen P, Baratz M, Fefer F, Gilat T. Low incidence of significant dysplasia in a successful endoscopic surveillance program of patients with ulcerative colitis. Gastroenterology 1995; 108: 1361-1370 PubMed
40 Nugent FW, Haggitt RC, Gilpin PA. Cancer surveillance in ulcerative colitis. Gastroenterology 1991; 100: 1241-1248
41 Rubin PH, Friedman S, Harpaz N, Goldstein E, Weiser J, Schiller J, Waye JD, Present DH. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology 1999; 117: 1295-1300 PubMed
42 Engelsgjerd M, Farraye FA, Odze RD. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis. Gastroenterology 1999; 117: 1288-1294; discussion 1488-1491 PubMed
43 Schneider A, Stolte M. Differential diagnosis of adenomas and dysplastic lesions in patients with ulcerative colitis. Z Gastroenterol 1993; 31: 653-656 PubMed
44 Odze RD, Farraye FA, Hecht JL, Hornick JL. Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis. Clin Gastroenterol Hepatol 2004; 2: 534-541 PubMed
45 Selaru FM, Xu Y, Yin J, Zou T, Liu TC, Mori Y, Abraham JM, Sato F, Wang S, Twigg C, Olaru A, Shustova V, Leytin A, Hytiroglou P, Shibata D, Harpaz N, Meltzer SJ. Artificial neural networks distinguish among subtypes of neoplastic colorectal lesions. Gastroenterology 2002; 122: 606-613 PubMed
46 Odze RD, Brown CA, Hartmann CJ, Noffsinger AE, Fogt F. Genetic alterations in chronic ulcerative colitis-associated adenoma-like DALMs are similar to non-colitic sporadic adenomas. Am J Surg Pathol 2000; 24: 1209-1216 PubMed
47 Riddell RH, Goldman H, Ransohoff DF, Appelman HD, Fenoglio CM, Haggitt RC, Ahren C, Correa P, Hamilton SR, Morson BC. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983; 14: 931-968 PubMed
48 Melville DM, Jass JR, Morson BC, Pollock DJ, Richman PI, Shepherd NA, Ritchie JK, Love SB, Lennard-Jones JE. Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome. Hum Pathol 1989; 20: 1008-1014 PubMed
49 Lim CH, Dixon MF, Vail A, Forman D, Lynch DA, Axon AT. Ten year follow up of ulcerative colitis patients with and without low grade dysplasia. Gut 2003; 52: 1127-1132 PubMed
50 Eaden J, Abrams K, McKay H, Denley H, Mayberry J. Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. J Pathol 2001; 194: 152-157 PubMed
51 Dixon MF, Brown LJ, Gilmour HM, Price AB, Smeeton NC, Talbot IC, Williams GT. Observer variation in the assessment of dysplasia in ulcerative colitis. Histopathology 1988; 13: 385-397 PubMed
52 Odze RD, Goldblum J, Noffsinger A, Alsaigh N, Rybicki LA, Fogt F. Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology. Mod Pathol 2002; 15: 379-386 PubMed
53 Connell WR, Lennard-Jones JE, Williams CB, Talbot IC, Price AB, Wilkinson KH. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994; 107: 934-944 PubMed
54 Riddell RH. Grading of dysplasia. Eur J Cancer 1995; 31A: 1169-1170 PubMed
55 Itzkowitz SH, Present DH. Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11: 314-321 PubMed
56 Ullman T, Croog V, Harpaz N, Sachar D, Itzkowitz S. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003; 125: 1311-1319 PubMed
57 Lennard-Jones JE, Melville DM, Morson BC, Ritchie JK, Williams CB. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990; 31: 800-806 PubMed
58 Ullman TA, Loftus EV Jr, Kakar S, Burgart LJ, Sandborn WJ, Tremaine WJ. The fate of low grade dysplasia in ulcerative colitis. Am J Gastroenterol 2002; 97: 922-927 PubMed
59 Befrits R, Ljung T, Jaramillo E, Rubio C. Low-grade dysplasia in extensive, long-standing inflammatory bowel disease: a follow-up study. Dis Colon Rectum 2002; 45: 615-620 PubMed
60 Woolrich AJ, DaSilva MD, Korelitz BI. Surveillance in the routine management of ulcerative colitis: the predictive value of low-grade dysplasia. Gastroenterology 1992; 103: 431-438 PubMed
61 Choi PM, Nugent FW, Schoetz DJ Jr, Silverman ML, Haggitt RC. Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology 1993; 105: 418-424 PubMed
62 Karlen P, Kornfeld D, Brostrom O, Lofberg R, Persson PG, Ekbom A. Is colonoscopic surveillance reducing colorectal cancer mortality in ulcerative colitis? A population based case control study. Gut 1998; 42: 711-714 PubMed
63 Griffiths AM, Sherman PM. Colonoscopic surveillance for cancer in ulcerative colitis: a critical review. J Pediatr Gastroenterol Nutr 1997; 24: 202-210 PubMed
64 Itzkowitz SH. Cancer prevention in patients with inflammatory bowel disease. Gastroenterol Clin North Am 2002; 31: 1133-1144 PubMed
65 Friedman S, Rubin PH, Bodian C, Goldstein E, Harpaz N, Present DH. Screening and surveillance colonoscopy in chronic Crohn's colitis. Gastroenterology 2001; 120: 820-826 PubMed
66 Gumaste V, Sachar DB, Greenstein AJ. Benign and malignant colorectal strictures in ulcerative colitis. Gut 1992; 33: 938-941 PubMed
67 Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S, Nafe B, Jung M, Galle PR, Neurath MF. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003; 124: 880-888 PubMed
68 Rutter MD, Saunders BP, Schofield G, Forbes A, Price AB, Talbot IC. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004; 53: 256-260 PubMed
69 Ochsenkuhn T, Tillack C, Stepp H, Diebold J, Ott SJ, Baumgartner R, Brand S, Goke B, Sackmann M. Low frequency of colorectal dysplasia in patients with long-standing inflammatory bowel disease colitis: detection by fluorescence endoscopy. Endoscopy 2006; 38: 477-482 PubMed
70 Itzkowitz SH. Molecular biology of dysplasia and cancer in inflammatory bowel disease. Gastroenterol Clin North Am 2006; 35: 553-571 PubMed
71 Itzkowitz SH, Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology 2004; 126: 1634-1648 PubMed
72 Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol 2005; 100: 1345-1353 PubMed
73 Velayos FS, Loftus EV Jr, Jess T, Harmsen WS, Bida J, Zinsmeister AR, Tremaine WJ, Sandborn WJ. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: A case-control study. Gastroenterology 2006; 130: 1941-1949 PubMed
74 Matula S, Croog V, Itzkowitz S, Harpaz N, Bodian C, Hossain S, Ullman T. Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine. Clin Gastroenterol Hepatol 2005; 3: 1015-1021 PubMed
75 Freudenheim JL, Graham S, Marshall JR, Haughey BP, Cholewinski S, Wilkinson G. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991; 20: 368-374 PubMed
76 Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA, Speizer FE, Willett WC. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993; 85: 875-884 PubMed
77 Lashner BA, Heidenreich PA, Su GL, Kane SV, Hanauer SB. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study. Gastroenterology 1989; 97: 255-259 PubMed
78 Lashner BA, Provencher KS, Seidner DL, Knesebeck A, Brzezinski A. The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterology 1997; 112: 29-32 PubMed
79 Tung BY, Emond MJ, Haggitt RC, Bronner MP, Kimmey MB, Kowdley KV, Brentnall TA. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 2001; 134: 89-95 PubMed
80 Pardi DS, Loftus EV Jr, Kremers WK, Keach J, Lindor KD. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003; 124: 889-893 PubMed
81 Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N Engl J Med 2005; 352: 2184-2192 PubMed
82 Greenstein AJ, Sachar D, Pucillo A, Kreel I, Geller S, Janowitz HD, Aufses A Jr. Cancer in Crohn's disease after diversionary surgery. A report of seven carcinomas occurring in excluded bowel. Am J Surg 1978; 135: 86-90
83 Sjodahl RI, Myrelid P, Soderholm JD. Anal and rectal cancer in Crohn's disease. Colorectal Dis 2003; 5: 490-495
84 Ky A, Sohn N, Weinstein MA, Korelitz BI. Carcinoma arising in anorectal fistulas of Crohn's disease. Dis Colon Rectum 1998; 41: 992-996 PubMed
85 Connell WR, Sheffield JP, Kamm MA, Ritchie JK, Hawley PR, Lennard-Jones JE. Lower gastrointestinal malignancy in Crohn's disease. Gut 1994; 35: 347-352 PubMed
86 Solem CA, Harmsen WS, Zinsmeister AR, Loftus EV Jr. Small intestinal adenocarcinoma in Crohn's disease: a case- control study. Inflamm Bowel Dis 2004; 10: 32-35 PubMed
87 Ekbom A, Helmick C, Zack M, Adami HO. Extracolonic malignancies in inflammatory bowel disease. Cancer 1991; 67: 2015-2019 PubMed
88 Munkholm P, Langholz E, Davidsen M, Binder V. Intestinal cancer risk and mortality in patients with Crohn's disease. Gastroenterology 1993; 105: 1716-17123 PubMed
89 Fireman Z, Grossman A, Lilos P, Hacohen D, Bar Meir S, Rozen P, Gilat T. Intestinal cancer in patients with Crohn's disease. A population study in central Israel. Scand J Gastroenterol 1989; 24: 346-350 PubMed
90 Fielding JF, Prior P, Waterhouse JA, Cooke WT. Malignancy in Crohn's disease. Scand J Gastroenterol 1972; 7: 3-7
91 Persson PG, Karlen P, Bernell O, Leijonmarck CE, Brostrom O, Ahlbom A, Hellers G. Crohn's disease and cancer: a population-based cohort study. Gastroenterology 1994; 107: 1675-1679 PubMed
92 Gullberg K, Stahlberg D, Liljeqvist L, Tribukait B, Reinholt FP, Veress B, Lofberg R. Neoplastic transformation of the pelvic pouch mucosa in patients with ulcerative colitis. Gastroenterology 1997; 112: 1487-1492 PubMed
93 Thompson-Fawcett MW, Marcus V, Redston M, Cohen Z, McLeod RS. Risk of dysplasia in long-term ileal pouches and pouches with chronic pouchitis. Gastroenterology 2001; 121: 275-281 PubMed
94 Herline AJ, Meisinger LL, Rusin LC, Roberts PL, Murray JJ, Coller JA, Marcello PW, Schoetz DJ. Is routine pouch surveillance for dysplasia indicated for ileoanal pouches? Dis Colon Rectum 2003; 46: 156-159 PubMed
95 O'Riordain MG, Fazio VW, Lavery IC, Remzi F, Fabbri N, Meneu J, Goldblum J, Petras RE. Incidence and natural history of dysplasia of the anal transitional zone after ileal pouch-anal anastomosis: results of a five-year to ten-year follow- up. Dis Colon Rectum 2000; 43: 1660-1665 PubMed
96 Mir-Madjlessi SH, Farmer RG, Easley KA, Beck GJ. Colorectal and extracolonic malignancy in ulcerative colitis. Cancer 1986; 58: 1569-1574 PubMed
97 Mellemkjaer L, Olsen JH, Frisch M, Johansen C, Gridley G, McLaughlin JK. Cancer in patients with ulcerative colitis. Int J Cancer 1995; 60: 330-333 PubMed
98 Karlen P, Lofberg R, Brostrom O, Leijonmarck CE, Hellers G, Persson PG. Increased risk of cancer in ulcerative colitis: a population-based cohort study. Am J Gastroenterol 1999; 94: 1047-1052 PubMed
99 Greenstein AJ, Gennuso R, Sachar DB, Heimann T, Smith H, Janowitz HD, Aufses AH Jr. Extraintestinal cancers in inflammatory bowel disease. Cancer 1985; 56: 2914-2921 PubMed
100 Caspi O, Polliack A, Klar R, Ben-Yehuda D. The association of inflammatory bowel disease and leukemia--coincidence or not? Leuk Lymphoma 1995; 17: 255-262 PubMed
101 Askling J, Brandt L, Lapidus A, Karlen P, Bjorkholm M, Lofberg R, Ekbom A. Risk of haematopoietic cancer in patients with inflammatory bowel disease. Gut 2005; 54: 617-622 PubMed
102 Greenstein AJ, Mullin GE, Strauchen JA, Heimann T, Janowitz HD, Aufses AH Jr, Sachar DB. Lymphoma in inflammatory bowel disease. Cancer 1992; 69: 1119-1123 PubMed
103 Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46: 3151-3158
104 Ljung T, Karlen P, Schmidt D, Hellstrom PM, Lapidus A, Janczewska I, Sjoqvist U, Lofberg R. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004; 53: 849-853 PubMed
105 Sandborn WJ, Loftus EV. Balancing the risks and benefits of infliximab in the treatment of inflammatory bowel disease. Gut 2004; 53: 780-782 PubMed
106 Bebb JR, Logan RP. Review article: does the use of immunosuppressive therapy in inflammatory bowel disease increase the risk of developing lymphoma? Aliment Pharmacol Ther 2001; 15: 1843-1849 PubMed
107 Aithal GP, Mansfield JC. Review article: the risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment. Aliment Pharmacol Ther 2001; 15: 1101-1108 PubMed
108 Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343: 1249-1252 PubMed
109 Bouhnik Y, Lemann M, Mary JY, Scemama G, Tai R, Matuchansky C, Modigliani R, Rambaud JC. Long-term follow-up of patients with Crohn's disease treated with azathioprine or 6-mercaptopurine. Lancet 1996; 347: 215-219 PubMed
110 Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002; 16: 1225-1232 PubMed
111 Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999; 94: 3248-3253 PubMed
112 Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn's disease: benefits outweigh the risk of lymphoma. Gastroenterology 2000; 118: 1018-1024 PubMed
113 Farrell RJ, Ang Y, Kileen P, O'Briain DS, Kelleher D, Keeling PW, Weir DG. Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low. Gut 2000; 47: 514-519 PubMed
114 Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005; 54: 1121-1125 PubMed
115 Disanti W, Rajapakse RO, Korelitz BI, Panagopoulos G, Bratcher J. Incidence of neoplasms in patients who develop sustained leukopenia during or after treatment with 6-mercaptopurine for inflammatory bowel disease. Clin Gastroenterol Hepatol 2006; 4: 1025-1029 PubMed
116 Brentnall TA. Molecular underpinnings of cancer in ulcerative colitis. Curr Opin Gastroenterol 2003; 19: 64-68 PubMed
117 Ahlquist DA, Skoletsky JE, Boynton KA, Harrington JJ, Mahoney DW, Pierceall WE, Thibodeau SN, Shuber AP. Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel. Gastroenterology 2000; 119: 1219-1227 PubMed
118 Tagore KS, Lawson MJ, Yucaitis JA, Gage R, Orr T, Shuber AP, Ross ME. Sensitivity and specificity of a stool DNA multitarget assay panel for the detection of advanced colorectal neoplasia. Clin Colorectal Cancer 2003; 3: 47-53 PubMed
S- Editor Liu Y L- Editor Alpini GD E- Editor Li JL