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[55
]. 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 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[53
]. 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.
Suggested management scheme for dysplasia. Modified from Ref 71. With permission.
Patients who have only had small intestinal Crohn’s disease without colonic involvement are not considered to be at high risk for CRC. For patients with Crohn’s colitis, much less is known. To date, only one practice-based retrospective surveillance study has been reported in patients with Crohn’s colitis[65
]. Of 259 patients with Crohn’s 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 Crohn’s colitis. An important question that remains to be clarified is whether patients with dysplasia or cancer in the setting of segmental Crohn’s 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 Crohn’s 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[66
]. However, since most strictures in Crohn’s 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[65
]. 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 demonstrated 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[67
], 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[68
]. 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[69
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)[70
]. 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[71
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[72
]. 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[22
], and others confirm this observation[73
], steroids cannot be used long-term for chemoprevention. There appears to be no chemopreventive activity of 6-mercaptopurine or azathioprine[74
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[79
]. 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
]. 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[81
]. 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[74
Small bowel cancer in IBD
Most cancers of the small bowel in Crohn’s disease are adenocarcinoma, usually in the terminal ileum or jejunum. The most common clinical presentation of small bowel cancer is intestinal obstruction[82
]. Other important symptoms include diarrhea, weight loss, and abdominal fistulae. These symptoms are also found in Crohn’s disease. Risk factors for developing carcinoma in small bowel segments of involved mucosa in patients with Crohn’s 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[86
A number of studies have demonstrated an increased risk of developing adenocarcinoma of the small intestine with small intestinal Crohn’s 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[87
], the investigators reported only one observed case compared with 0.3 expected cases, but the confidence interval was wide. In the Copenhagen study[88
], two cases were observed vs
0.04 expected cases, a 50-fold increased occurrence. In the Tel Aviv study[89
], 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[90
]. 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[91
]. 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)[4
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[92
], but this has not been shown in all series[93
]. 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[94
]. 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[95
]. 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 Crohn’s disease[85
]. Worsening perianal symptoms in such patients should warrant heightened vigilance for this tumor which often requires examination under anesthesia for adequate tissue diagnosis.
An increased risk for hepatobiliary cancers in patients with UC has been found in several[4,96–98
] but not all[87
] 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[96
] and The Mount Sinai Hospital[99
], as well as other centers[100
] reported an increase in leukemia in patients with UC. A recent large cohort study from Sweden[101
], 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 Crohn’s 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[97
] and Canada[4
] 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[96
] and several population-based studies[87,91,97,98
] do not support the notion that patients with UC or Crohn’s disease are at increased risk of lymphoma. However, a population-based study from Canada reported an increased rate of lymphoma among male patients with Crohn’s disease[4
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 Crohn’s 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 naïve (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[114
]. Another recent study showed a statistically significant increase in the development of malignancies among IBD patients treated with 6-MP who developed sustained leucopenia[115