Introduction

Patients with inflammatory bowel disease (IBD) areat an increased risk for colorectal cancer (CRC)[1–4], but the quantisation of the risk of CRC in thisspecific population varies widely in different studies.However, CRC complicating ulcerative colitis (UC)and Crohn’s disease (CD) only accounts for 1–2% ofall cases of CRC in the general population. Most casesof CRC are either sporadic (65–85%) or familial(10–30%; Fig. 1) [3–4].

CRC is considered a serious complication of thedisease and accounts for approximately 15% of alldeaths in IBD patients [5]. The mortality in patientsdiagnosed with CRC who are also diagnosed withIBD is higher than for sporadic CRC [6]. However,much more is known about the risk in UC. The inci-dence of colorectal cancer in patients with ulcerativecolitis is higher than in the general population. In ameta-analysis, the overall prevalence of CRC in anyUC patient, based on 116 studies, was estimated to be3.7%. The incidence rate corresponded to cumulativeprobabilities of 2% by 10 years, 8% by 20 years and18% by 30 years [7].

The major risk factors for the development of CRCinclude young age at onset of IBD [1], extensive dis-ease [8] and long disease duration [5]. It is biologi-cally plausible that the excess cancer risk is second-ary to chronic inflammation and it is recognised thatduration of colitis is an important risk factor forCRC. Rutter et al. [9] showed for the first time that

increasing severity of colonic inflammation is associ-ated with an increase in the rate of colorectal neopla-sia in UC. Patients with disease extending to thehepatic flexure or more proximally have the greatestrisk of CRC [10–12]. Most studies have found that therisk of CRC increases after 15 to 20 years; approxi-mately one decade later than in pancolitis in patientswith colitis confined to the left colon [8]. Patientswith ulcerative proctitis and proctosigmoiditis areprobably not at increased risk for CRC [13]. Anincreased risk of CRC has been observed in patientswith UC complicated by primary sclerosing cholangi-tis. In these cases, cancer was more likely to be in theright colon, suggesting a possible role of bile acids inoncogenesis [14].

The evidence for other potential risk factors isscarce. Smoke [15], folate depletion [16–17] and apositive family history of colon cancer [18] mayaffect the occurrence of CRC. A hypothesis has beenput forward according to which UC, CD and CRCoccur in predisposed patients because of a mixture ofgenetic and environmental factors. One study hasshown that relatives of patients with both IBD andCRC have an 80% increased risk of CRC [19]. In ourstudy, there is no statistically significant differencebetween IBD and control cases of family members asfar as prevalence of malignant colorectal, digestiveextra-colonic or extra-digestive tract tumours [20].Another recent study has investigated the prevalenceof all malignancies in first-degree relatives of CDpatients. The result showed a higher prevalence ofbreast cancer in female relatives, mainly in mothers,of CD patients compared with controls. The presenceof breast cancer was not associated with any specificphenotype of the CD [21].

As in UC, Crohn’s disease of the colon carries anincreased risk of CRC. Ekbom et al. [1] found a rela-tive risk of 5.6% for CRC among patients with CD,whereas in another Swedish patient cohort study,Persson et al. [22] did not find that the populationrelative risk increased. Similarly, Fireman et al. [23]from Israel and Jess et al. [24] in the Danish cohort,did not find an increased risk of CRC among their

IBD: Cancer Risk and Surveillance

Gabriele Riegler, Ilaria Esposito

Fig. 1. Distribution of CRC

46 G. Riegler, I. Esposito

patients with CD. Although analyzing subgroupswithin the CD study meant that there were few can-cers identified, when patients with CD of >10-yearduration were analyzed, the relative risk for CRC was4.8%. For those patients with at least 10 years of dis-ease and no surgery within the first 10 years, the rel-ative risk was 8.3%. Thus, even among this reported-ly negative study, when variables such as diseaseduration and possibly disease extent (based on nosurgery) are analysed, the relative risk increases [5].In the study of Gillen et al. [25], however, it appearsthat the malignant potential in CD and UC is of thesame order of magnitude. Cancer developed ininflamed areas in both diseases, and was thus locatedin the right colon in 49% of patients with CD com-pared with 36% with UC, reflecting the difference ininflammatory sites in the two cases. Adenocarcino-mas develop only in affected segments of the smallintestine, and are difficult to diagnose at an earlystage because the radiological appearance is similarto that of stricturing CD.

Pathogenesis of CRC in IBD

The pathogenesis of CRC in IBD is poorly under-stood. However, several lines of evidence suggest thatthe pathobiology is different than sporadic CRC:1. the mean age of developing CRC in the setting of

IBD is lower than sporadic CRC (40–50 vs. 60years).

2. Dysplasia in UC is preceded by a long history ofchronic inflammation and can be found at distantsites from the cancer. In contrast, dysplasia in spo-radic CRC is usually associated with a discretepolyp without inflammation.

3. Mutations in the ras protooncogene are present in40–60% of sporadic CRC and are probably an earlyevent; in contrast, these mutations are less fre-quently observed in cancer associated with UC,and are probably a late event [26–27].

4. Loss of heterozygosity for the p53 gene and srcactivation occur earlier in cancers associated withIBD than in sporadic CRC. Src activity in UC cor-relates with the degree of dysplasia [28].

5. Abnormalities of the p53 locus are absent in non-dysplastic mucosa of patients with sporadic CRC.In contrast, non-dysplastic mucosa in UC fre-quently has aneuploid DNA content and mayshow clones of cells with loss of heterozygosity ofthe p53 gene [29].It is generally accepted that CRC in IBD is preced-

ed by dysplasia, which is defined as unequivocal neo-plastic epithelium and is currently the most impor-tant and best-defined marker of an increased risk ofmalignancy. Dysplasia is present in >70% of UC

patients with carcinoma. Although it may occur inany portion of the colon, it typically parallels thelocation of cancer arising from chronically inflamedmucosa [30–32]. From an endoscopic viewpoint, dys-plasia is characterised as flat (endoscopically invisi-ble but detected in mucosal specimens) or raised(endoscopically visible), in which case “dysplasiaassociated lesions or mass” (DALM) is applied, aterm that was coined by Blackstone et al. in 1981 [33].In their study, 12 of 112 patients with long-standingUC were found to have a DALM, and of these, seven(58%) had carcinoma. Given the strong associationwith cancer, the presence of DALM constituted astrong indication for colectomy, which has becomethe standard therapy for this type of lesion. DALMare a heterogeneous population of tumours that mayendoscopically appear as a plaque, mass (irregular,broad-based or strictured lesions), a discrete sessilenodule, or polyp. The cancer risk is not equal amongthese various subtypes. Unfortunately, most of theprevious studies of UC associated DALMs failed toevaluate these lesions in relation to their grossappearance. For instance, there is one specific sub-type of discrete DALM that endoscopically and histo-logically resembles a sporadic adenoma (isolateddysplastic nodule or polyp) and, as such, poses a dif-ficult diagnostic challenge both to clinicians and topathologists [34]. This is a critically important dis-tinction, because an adenoma-like DALM is atumour that arises as a result of UC and, thus, is anindication for colectomy, whereas an adenoma whichis also by definition a “polypoid dysplastic lesion”,the development of which is unrelated to the under-lying chronic colitis (but coincidentally exists withit), is usually treated by polypectomy.

Since both UC and sporadic adenomas (SA) arenot uncommon disorders, it is not surprising thatgastroenterologists regularly encounter patients whohave both conditions. Sporadic adenomas coexistwith UC if they are located next (proximal) to thecolitis because UC-related dysplasia does not developfrom non-inflamed epithelium. UC associated ade-noma-like DALMs were classified as lesions that werelocated within histologically proven areas of colitisand were associated with either synchronous ormetachronous flat dysplasia or adenocarcinoma [35].

A number of clinical, histologic and molecular fea-tures have been studied to help make a distinctionbetween DALM and SA:1. patients with non-adenoma-like DALM are more

likely to be younger and have a longer duration ofdisease, more extensive disease, and larger lesions[36].

2. Lesions that appear endoscopically as adenomas(pedunculated or sessile) rather than having othercharacteristics (such as flat, ulcerated, or plaque-

IBD: Cancer Risk and Surveillance 47

like appearance), even if found within an area ofhistologic colitis, may have a favourable progno-sis with endoscopic removal and close follow-up[35, 37, 38].In addition to the clinical and histologic features

described above, several molecular markers havebeen proposed for distinguishing DALM from SA.Two of these are beta catenin and p53 [39–40]. Betacatenin is a cell membrane protein that accumulatesmore frequently in the nuclei of cells within sporadiccolon cancer as compared to DALM. Mutations withp53 (a tumour suppressor gene) occur more fre-quently in DALM than sporadic adenomas. Severalstudies have provided evidence that p53 polymor-phism at codon 72 (Arg and Pro alleles) may be asso-ciated with a high risk of malignancies. A recentstudy investigated Arg72Pro polymorphism in UCand found that p53 Pro homozygosis was more fre-quent in patients who had a continuous disease and,therefore, may also favour the progression from dys-plasia to colon cancer [41].

The predictive value of dysplasia has been studiedin UC. Although dysplasia is a marker for future orconcurrent malignancy, it can also regress or remainstable for long periods. Most patients with dysplasiado not have cancer and dysplasia is absent in thecolonic regions distant from the malignancy in25–30% of patients [42-43].

The association between dysplasia and CRC in CDappears to be similar to that in UC. Dysplasia is pres-ent in 83% of patients diagnosed with CRC, and dys-plasia distant from the cancer is found in 23–70%. Incontrast, dysplasia is much less common in colecto-my specimens of patients with CD than without CRC,and has occurred in only 2% of the specimens in oneseries [44–45].

Interpretation of biopsy samples may be con-founded by interobserver variation in the recogni-tion and grading of dysplasia. A uniform terminolo-gy for dysplasia in IBD has been proposed [29]. Theclassification categories histology as:1. negative.2. Indefinite (with subgroups of probably negative,

unknown, and probably positive.3. Positive (with subgroups of low grade and high-

grade dysplasia).Dysplasia may be difficult to distinguish from

inflammation and regeneration on histologic sec-tions. As a result, the presence of dysplasia should beconfirmed by an experienced pathologist. The crite-ria for dysplasia stress the uniform clonal nature ofdysplastic changes, which affects equally all parts ofthe crypt and surface epithelium. In contrast, regen-erative changes are usually most prominent at thebase of the crypts and show evidence of maturationas they migrate toward the crypt surface.

Other architectural and cytological abnormalitiesseen in regards to dysplastic epithelium include [29]:increased epithelium proliferation and mitoses;increased epithelial height; branching of crypts;back-to-back glandular formation; variation in thesize and shape of nuclei; increased nuclear/cytoplas-matic ratio; altered nuclear polarity globet cells.

Surveillance

Dysplastic epithelium may be a marker for coexistingmalignancy, and provides the rationale for surveil-lance. The optimal surveillance strategy remains con-troversial [45]. Surveillance colonoscopy in IBD isadvocated for early diagnosis of neoplasia, but isimperfect because some patients develop cancerdespite surveillance. In effect, a few reports haveshown conflicting results and these studies suggestthat surveillance leads to the detection of early-stagecancer in only a minority of patients and a significantnumber of patients develop cancer at an advancedstage despite surveillance.

The American Gastroenterological Association(AGA) recommends that colonoscopic surveillanceshould begin after 8 years in patients with pancolitisand 15 years in patients with colitis involving the leftcolon. Colonoscopy should be repeated every 1–2 years.

The American College of Gastroenterology (ACG)recommends annual surveillance colonoscopy begin-ning after 8–10 years of disease. Multiple biopsiesshould be obtained at regular intervals. The findingof definite dysplasia is an indication for colectomy.Patients whose biopsies are indefinite for dysplasiashould undergo repeat surveillance colonoscopy at ashorter interval.

The American Society for GastrointestinalEndoscopy (ASGE) recommends that patients withUC who have pancolitis should begin surveillancecolonoscopy after 8 years of disease. Four biopsiesshould be obtained every 10 cm from the cecum tothe rectum. In addiction, any suspicious lesions ormasses should be biopsied. Colonoscopy should berepeated every 1–3 years. The finding of carcinomaor high-grade dysplasia is an indication for colecto-my. Colectomy is also indicated for any degree ofdysplasia associated with lesion or mass. However, inpatients in whom colectomy is not feasible or is unac-ceptable, frequent surveillance, every 3–6 months, isconsidered an acceptable alternative. For patientswith left-sided colitis, the ASGE recommends thatsurveillance should begin after 15 years of disease.Surveillance is not indicated in ulcerative proctitis. InCD, the risk of colorectal cancer is increased only inregard to Crohn’s colitis. Surveillance colonoscopyand biopsy for dysplasia should be offered to patients

48 G. Riegler, I. Esposito

with longstanding disease. Furthermore, a reductionin mortality due to surveillance has not yet beenestablished.

On the other hand, prophylactic colectomy is amethod to prevent the development of CRC in IBD.The development of the stapling of the ileal pouch-anal anastomosis with preservation of the anal tran-sitional zone is an important advancement in surgi-cal treatment, but remains controversial because ofconcerns about the potential risk of dysplasia andcancer. The risk factor for carcinoma is inflammationin the small intestinal and rectal mucosa. Pouchitis isthe most frequent late complication and clearly relat-ed to a worse outcome. The etiology of pouchitisremains unknown. Possible causes are fecal stasisresulting in bacterial overgrowth and infection [46],microbial imbalance [47], production of volatile fattyacids, ischemia [48], oxygen-free radical injury [49],nitric oxide [50] and deprivation of short chain fattyacids [51]. Penna et al. [52] reported a strong corre-lation between primary sclerosing cholangitis andpouchitis, suggesting a common link in their patho-genesis. Teixeira et al. [53] showed that pouchitis wasmore frequent in patients with extra-intestinal mani-festations. Acute pouchitis was more frequent thanchronic pouchitis described by others.

Conclusion

In conclusion, patients with UC who undergo an ilealanal pouch operation also require surveillance. Morerecent research has focused on the chemopreventionof CRC in IBD using aminosalicylate (5-ASA) prepa-rations. Several retrospective correlative studies havesuggested that the long-term use of 5-ASA in IBDpatients may significantly reduce the risk of develop-ment of CRC. Moody et al. [54] demonstrated thatpatients with UC who did not comply with 5-ASAtherapies were significantly more likely to developCRC than their counterparts. Eaden et al. [55] foundthat regular 5-ASA therapy reduces cancer risk by75% in IBD patients. Mesalazine at a dose of 1.2 g/dayor greater reduced CRC risk by 91% compared to notreatment and was also supportive when taken atlower doses. They concluded that the benefit of regu-lar consumption of 5-ASA was equal to frequent vis-its to a hospital physician.

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