IBD: Cancer Risk and Surveillance

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Introduction

Patients with inflammatory bowel disease (IBD) are at an increased risk for colorectal cancer (CRC) [1–4], but the quantisation of the risk of CRC in this specific population varies widely in different studies.

However, CRC complicating ulcerative colitis (UC) and Crohn’s disease (CD) only accounts for 1–2% of all cases of CRC in the general population. Most cases of CRC are either sporadic (65–85%) or familial (10–30%; Fig. 1) [3–4].

CRC is considered a serious complication of the disease and accounts for approximately 15% of all deaths in IBD patients [5]. The mortality in patients diagnosed with CRC who are also diagnosed with IBD is higher than for sporadic CRC [6]. However, much more is known about the risk in UC. The incidence of colorectal cancer in patients with ulcerative colitis is higher than in the general population. In a meta-analysis, the overall prevalence of CRC in any UC patient, based on 116 studies, was estimated to be 3.7%. The incidence rate corresponded to cumulative probabilities of 2% by 10 years, 8% by 20 years and 18% by 30 years [7].

The major risk factors for the development of CRC include young age at onset of IBD [1], extensive disease [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 that duration of colitis is an important risk factor for CRC. Rutter et al. [9] showed for the first time that

increasing severity of colonic inflammation is associated with an increase in the rate of colorectal neoplasia in UC. Patients with disease extending to the hepatic flexure or more proximally have the greatest risk of CRC [10–12]. Most studies have found that the risk of CRC increases after 15 to 20 years; approximately one decade later than in pancolitis in patients with colitis confined to the left colon [8]. Patients with ulcerative proctitis and proctosigmoiditis are probably not at increased risk for CRC [13]. An increased risk of CRC has been observed in patients with UC complicated by primary sclerosing cholangitis. In these cases, cancer was more likely to be in the right colon, suggesting a possible role of bile acids in oncogenesis [14].

The evidence for other potential risk factors is scarce. Smoke [15], folate depletion [16–17] and a positive family history of colon cancer [18] may affect the occurrence of CRC. A hypothesis has been put forward according to which UC, CD and CRC occur in predisposed patients because of a mixture of genetic and environmental factors. One study has shown that relatives of patients with both IBD and CRC have an 80% increased risk of CRC [19]. In our study, there is no statistically significant difference between IBD and control cases of family members as far as prevalence of malignant colorectal, digestive extra-colonic or extra-digestive tract tumours [20].

Another recent study has investigated the prevalence of all malignancies in first-degree relatives of CD patients. The result showed a higher prevalence of breast cancer in female relatives, mainly in mothers, of CD patients compared with controls. The presence of breast cancer was not associated with any specific phenotype of the CD [21].

As in UC, Crohn’s disease of the colon carries an increased risk of CRC. Ekbom et al. [1] found a relative 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 population relative 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

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patients with CD. Although analyzing subgroups within the CD study meant that there were few cancers identified, when patients with CD of >10-year duration were analyzed, the relative risk for CRC was 4.8%. For those patients with at least 10 years of disease and no surgery within the first 10 years, the relative risk was 8.3%. Thus, even among this reported- ly negative study, when variables such as disease duration and possibly disease extent (based on no surgery) are analysed, the relative risk increases [5].

In the study of Gillen et al. [25], however, it appears that the malignant potential in CD and UC is of the same order of magnitude. Cancer developed in inflamed areas in both diseases, and was thus located in the right colon in 49% of patients with CD compared with 36% with UC, reflecting the difference in inflammatory sites in the two cases. Adenocarcino- mas develop only in affected segments of the small intestine, and are difficult to diagnose at an early stage because the radiological appearance is similar to 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 that the 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. 60 years).

2. Dysplasia in UC is preceded by a long history of chronic inflammation and can be found at distant sites from the cancer. In contrast, dysplasia in sporadic CRC is usually associated with a discrete polyp without inflammation.

3. Mutations in the ras protooncogene are present in 40–60% of sporadic CRC and are probably an early event; in contrast, these mutations are less frequently observed in cancer associated with UC, and are probably a late event [26–27].

4. Loss of heterozygosity for the p53 gene and src activation occur earlier in cancers associated with IBD 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 frequently has aneuploid DNA content and may show clones of cells with loss of heterozygosity of the p53 gene [29].

It is generally accepted that CRC in IBD is preceded by dysplasia, which is defined as unequivocal neoplastic epithelium and is currently the most important and best-defined marker of an increased risk of malignancy. Dysplasia is present in >70% of UC

patients with carcinoma. Although it may occur in any portion of the colon, it typically parallels the location of cancer arising from chronically inflamed mucosa [30–32]. From an endoscopic viewpoint, dysplasia is characterised as flat (endoscopically invisi- ble but detected in mucosal specimens) or raised (endoscopically visible), in which case “dysplasia associated lesions or mass” (DALM) is applied, a term that was coined by Blackstone et al. in 1981 [33].

In their study, 12 of 112 patients with long-standing UC were found to have a DALM, and of these, seven (58%) had carcinoma. Given the strong association with cancer, the presence of DALM constituted a strong indication for colectomy, which has become the standard therapy for this type of lesion. DALM are a heterogeneous population of tumours that may endoscopically appear as a plaque, mass (irregular, broad-based or strictured lesions), a discrete sessile nodule, or polyp. The cancer risk is not equal among these various subtypes. Unfortunately, most of the previous studies of UC associated DALMs failed to evaluate these lesions in relation to their gross appearance. For instance, there is one specific sub- type of discrete DALM that endoscopically and histologically resembles a sporadic adenoma (isolated dysplastic nodule or polyp) and, as such, poses a difficult diagnostic challenge both to clinicians and to pathologists [34]. This is a critically important distinction, because an adenoma-like DALM is a tumour that arises as a result of UC and, thus, is an indication for colectomy, whereas an adenoma which is also by definition a “polypoid dysplastic lesion”, the development of which is unrelated to the under- lying chronic colitis (but coincidentally exists with it), is usually treated by polypectomy.

Since both UC and sporadic adenomas (SA) are not uncommon disorders, it is not surprising that gastroenterologists regularly encounter patients who have both conditions. Sporadic adenomas coexist with UC if they are located next (proximal) to the colitis because UC-related dysplasia does not develop from non-inflamed epithelium. UC associated adenoma-like DALMs were classified as lesions that were located within histologically proven areas of colitis and were associated with either synchronous or metachronous flat dysplasia or adenocarcinoma [35].

A number of clinical, histologic and molecular features have been studied to help make a distinction between DALM and SA:

1. patients with non-adenoma-like DALM are more likely to be younger and have a longer duration of disease, more extensive disease, and larger lesions [36].

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

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like appearance), even if found within an area of histologic 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 have been proposed for distinguishing DALM from SA.

Two of these are beta catenin and p53 [39–40]. Beta catenin is a cell membrane protein that accumulates more frequently in the nuclei of cells within sporadic colon cancer as compared to DALM. Mutations with p53 (a tumour suppressor gene) occur more frequently in DALM than sporadic adenomas. Several studies have provided evidence that p53 polymorphism at codon 72 (Arg and Pro alleles) may be associated with a high risk of malignancies. A recent study investigated Arg72Pro polymorphism in UC and found that p53 Pro homozygosis was more frequent in patients who had a continuous disease and, therefore, may also favour the progression from dysplasia to colon cancer [41].

The predictive value of dysplasia has been studied in UC. Although dysplasia is a marker for future or concurrent malignancy, it can also regress or remain stable for long periods. Most patients with dysplasia do not have cancer and dysplasia is absent in the colonic regions distant from the malignancy in 25–30% of patients [42-43].

The association between dysplasia and CRC in CD appears to be similar to that in UC. Dysplasia is present in 83% of patients diagnosed with CRC, and dysplasia distant from the cancer is found in 23–70%. In contrast, dysplasia is much less common in colectomy specimens of patients with CD than without CRC, and has occurred in only 2% of the specimens in one series [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]. The classification 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 be confirmed by an experienced pathologist. The crite- ria for dysplasia stress the uniform clonal nature of dysplastic changes, which affects equally all parts of the crypt and surface epithelium. In contrast, regen- erative changes are usually most prominent at the base of the crypts and show evidence of maturation as they migrate toward the crypt surface.

Other architectural and cytological abnormalities seen 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 the size and shape of nuclei; increased nuclear/cytoplas- matic ratio; altered nuclear polarity globet cells.

Surveillance

Dysplastic epithelium may be a marker for coexisting malignancy, and provides the rationale for surveillance. The optimal surveillance strategy remains controversial [45]. Surveillance colonoscopy in IBD is advocated for early diagnosis of neoplasia, but is imperfect because some patients develop cancer despite surveillance. In effect, a few reports have shown conflicting results and these studies suggest that surveillance leads to the detection of early-stage cancer in only a minority of patients and a significant number of patients develop cancer at an advanced stage despite surveillance.

The American Gastroenterological Association (AGA) recommends that colonoscopic surveillance should begin after 8 years in patients with pancolitis and 15 years in patients with colitis involving the left colon. 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 biopsies should be obtained at regular intervals. The finding of definite dysplasia is an indication for colectomy.

Patients whose biopsies are indefinite for dysplasia should undergo repeat surveillance colonoscopy at a shorter interval.

The American Society for Gastrointestinal Endoscopy (ASGE) recommends that patients with UC who have pancolitis should begin surveillance colonoscopy after 8 years of disease. Four biopsies should be obtained every 10 cm from the cecum to the rectum. In addiction, any suspicious lesions or masses should be biopsied. Colonoscopy should be repeated every 1–3 years. The finding of carcinoma or high-grade dysplasia is an indication for colectomy. Colectomy is also indicated for any degree of dysplasia associated with lesion or mass. However, in patients in whom colectomy is not feasible or is unac- ceptable, frequent surveillance, every 3–6 months, is considered an acceptable alternative. For patients with left-sided colitis, the ASGE recommends that surveillance should begin after 15 years of disease.

Surveillance is not indicated in ulcerative proctitis. In CD, the risk of colorectal cancer is increased only in regard to Crohn’s colitis. Surveillance colonoscopy and biopsy for dysplasia should be offered to patients

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with longstanding disease. Furthermore, a reduction in mortality due to surveillance has not yet been established.

On the other hand, prophylactic colectomy is a method 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 of concerns about the potential risk of dysplasia and cancer. The risk factor for carcinoma is inflammation in the small intestinal and rectal mucosa. Pouchitis is the most frequent late complication and clearly related to a worse outcome. The etiology of pouchitis remains unknown. Possible causes are fecal stasis resulting in bacterial overgrowth and infection [46], microbial imbalance [47], production of volatile fatty acids, ischemia [48], oxygen-free radical injury [49], nitric oxide [50] and deprivation of short chain fatty acids [51]. Penna et al. [52] reported a strong corre- lation between primary sclerosing cholangitis and pouchitis, suggesting a common link in their pathogenesis. Teixeira et al. [53] showed that pouchitis was more frequent in patients with extra-intestinal mani- festations. Acute pouchitis was more frequent than chronic pouchitis described by others.

Conclusion

In conclusion, patients with UC who undergo an ileal anal pouch operation also require surveillance. More recent research has focused on the chemoprevention of CRC in IBD using aminosalicylate (5-ASA) prepa- rations. Several retrospective correlative studies have suggested that the long-term use of 5-ASA in IBD patients may significantly reduce the risk of development of CRC. Moody et al. [54] demonstrated that patients with UC who did not comply with 5-ASA therapies were significantly more likely to develop CRC than their counterparts. Eaden et al. [55] found that regular 5-ASA therapy reduces cancer risk by 75% in IBD patients. Mesalazine at a dose of 1.2 g/day or greater reduced CRC risk by 91% compared to no treatment and was also supportive when taken at lower doses. They concluded that the benefit of regular consumption of 5-ASA was equal to frequent vis- its to a hospital physician.

References

1. Ekbom A, Helmick C, Zack M et al (1990) Increased risk of large bowel cancer in Crohn’s disease with colonic involvement. Lancet 336:357–359

2. Langholz E, Munkholm P, Davidsen M et al (1992)

Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology 103:1444–1451 3. Choi PM, Zelig MP (1994) Similarity of colorectal can-

cer in CD and UC. Gut 35:950–954

4. Gyde S, Prior P, Dew MJ et al (1982) Mortality in ulcerative colitis. Gastroenterology 83:36–43

5. Munkholm P, Langholz E, Davidsen M, Binder V (1993) Intestinal cancer risk and mortality in patients with Crohn’s disease. Gastroenterology 105:1716–1723 6. Jess T, Winther KV, Munkholm P et al (2002) Mortali- ty and causes of death in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark. Gastroenterology 122:1808–1814

7. Eaden JA, Abrams KR, Mayberry JF (2001) The risk of colorectal cancer in ulcerative colitis: a meta analysis.

Gut 48:526–535

8. Ekbom A, Helmick C, Zack M, Ademi HO (1990) Ulcerative colitis and colorectal cancer. N Eng J Med 323:1228–1233

9. Rutter M, Saunders B, Wilkinson K et al (2004) Sever- ity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126:451–459

10. Gyde SN, Prior P, Allan RN et al (1988) Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centers. Gut 29:206

11. Lennard-Jones JE (1985) Cancer risk in ulcerative colitis: surveillance or surgery. Br J Surg 72(Suppl):84 12. Collins RH, Feldman M, Fordtran JS (1987) Colon can-

cer, dysplasia and surveillance in patients with ulcerative colitis: a critical review. N Engl J Med 316:1654 13. Levin B (1992) Inflammatory bowel disease and colon

cancer. Cancer 70:1313

14. Marchesa P, Lashner BA, Lavery IC et al (1997) The risk of cancer and dysplasia among ulcerative colitis patients with primary sclerosing cholangitis. Am J Gastroenterol 92:1285

15. Pinczowski D, Ekbom A, Baron J, et al (1994) Risk factors for colorectal cancer in patients with ulcertive colitis: a case-control study. Gastroenterology 107:117–120 16. Lashner BA, Provencher KS, Seidner DL et al (1997) The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis. Gastroenterol- ogy 112:29–32

17. Lashner BA, Heindereich PA, Su GL et al (1989) Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. Gastroen- terology 97:255–259

18. Nuako KW, Ahlquist DA, Mahoney DW et al (1998) Familial predisposition for colorectal cancer in chronic ulcerative colitis: a case-control study. Gastroen- terology 115:1079–1083

19. Askling J, Dickman PW, Karlen P et al (2001) Colorec- tal cancer rates among first-degree relatives of patients with inflammatory bowel disease: a population-based study. Lancet 357:262–266

20. Riegler G, Carratù R, Tartaglione MT et al (1988) Prevalence and relative risk of malignancy in relatives of inflammatory bowel disease patients an control subjects. J Clin Gastroenterol 27(3):211–214

21. Riegler G, Caserta L, Castiglione F et al (2006) Increased risk of breast cancer in first-degree relatives of Crohn's disease patients: an IG-IBD study. Dig Liv

(5)

Dis 38(1):18–23

22. Persson PG, Karlen P, Bernell O et al (1994) Crohn’s disease and cancer: a population-based cohort study.

Gastroenterology 107:1675–1679

23. Fireman Z, Grossman A, Lilos P et al (1989) Intestinal cancer in patients with Cron’s disease: a population study in cental Israel. Scand J Gastroenterol 24:346–350

24. Jess T, Winther K, Munkholm P et al (2000) Is there an increased risk of intestinal and extra intestinal cancer in patients with Crohn’s disease? A population based cohort followed from 1962 to 1997. Gastroenterology 118(Suppl 2):1472

25. Gillen CD, Walmsley RS, Prior R et al (1994) Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 35:651–5 26. Vogelstein B, Fearon ER, Hamilton SR et al (1988)

Genetic alteration during colorectal tumour development. N Engl J Med 319:525

27. Itzkowitz SH, Greenwald B, Meltzer SJ (1995) Colon carcinogenesis in inflammatory bowel disease.

Inflamm Bowel Dis 1:142

28. Burner GC, Rabinovitch PS, Haggit RC et al (1992) Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterolo- gy 103:1602

29. Riddell RH, Golman H, Ramsohoff DF et al (1983) Dysplasia in inflammatory bowel disease: standard- ized classification with provisional clinical applica- tion. Hum Pathol 14:931–968

30. Willenbucher RF (1996) Inflammatory bowel disease.

Semin Gastrointest Dis 7:94–104

31. Lennard-Jones JE, Nelville DM, Morson BC et al (1990) Precancer and cancer in extensive ulcerative colitis:

findings among 401 patients over 22 years. Gut 31:800–806

32. Goldman H (1996) Significance and detection of dysplasia in chronic colitis. Cancer 78:2261–2263 33. Blackstone MO, Riddell RH, Roger BHG et al (1982)

Dysplasia-associated lesion or mass (DALM) detected by colonscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 80:366–374 34. Torres C, Antonioli D, Odze RD et al (1998) Polypoid dysplasia and adenomas in inflammatory bowel disease. Am J Surg Pathol 22:275–284

35. Odze RD (1999) Adenomas and adenomas-like DALMs in chronic ulcerative colitis: a clinical, patho- logical and molecular review. Am J Gastroenterol 94:1746–1750

36. Suzuki K, Muto T, Shinozaki M et al (1998) Differen- tial diagnoses of dysplasia associated lesion or mass and coincidental adenoma in ulcerative colitis. Dis Colon Rectum 41:322

37. Engelsgjerd M, Farraye FA, Odze RD (1999) Polypec- tomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis. Gas- troenterology 117:1288

38. Rubin PH, Friedman S, Harpaz N et al (1999) Colonoscopy polypectomy in chronic colitis: conser- vative management after endoscopic resection of dysplastic polyps. Gastroenterology 117:1295

39. Morin PJ, Sparks AB, Korinek V et al (1997) Activation

of B-catenin-Tcf signaling in colon cancer by mutations in B-catenin or APC. Science 275:1787

40. Munemitsu S, Albert I, Souza B et al (1995) Regulation of intracellular beta-catenin levels by adenomatous polyposis coli (APC) tumour suppressor protein. Proc Natl Acad Sci USA 92:3046

41. Vietri MT, Riegler G, Pappalardo D et al (2006) The Arg72Pro p53 polymorphism influences the clinical outcome of ulcerative colitis. Lab Invest (In press) 42. Ramsohoff DF, Riddell RH, Levin B (1985) Ulcerative

colitis and colonic cancer: problems in assessing the diagnostic usefulness of mucosal dysplasia. Dis Colon Rectum 28:383

43. Taylor BA, Pemberton JH, Carpenter HA et al (1992) Dysplasia in chronic ulcerative colitis: implications for colonoscopic surveillance. Dis Colon Rectum 35:950 44. Warren R, Barwick KW (1983) Crohn’s colitis with

adenocarcinoma and dysplasia: report of a case and review of 100 small and large bowel resection for Crohn’s disease to detect incidence of dysplasia. Am J Surg Pathol 7:151

45. Provenzale D, Wong JB, Onken JE, Lipscomb J (1998) Performing a cost effectiveness analysis: surveillance of patients with ulcerative colitis. Am J Gastroenterol 93:872

46. Fonkalsrud EW, Phillips JD (1990) Reconstruction of malfunctioning ileoanal pouch procedures as an alternative to permanent ileostomy. Am J Surg 160:245–251 47. Ruseler-Van Embden JGH, Schouten WR (1994) Pou- chitis: result of microbial imbalance? Gut 35:658–664 48. Chaussade S, Denizot Y, Valleur P (1991) Presence of

Paf-acether in stool of patients with pouch ileoanal anastomosis and pouchitis. Gastroenterology 100:1509–1514

49. Levin KE, Pemberton JH, Phillips SF (1992) Role of oxygen free radicals in the etiology of pouchitis. Dis Colon Rectum 35:452–456

50. Kroesen AJ, John M, Schofelder G (1997) Expression of inducible nitric oxide syntase (iNOS) in pouchitis after ileoanal pouch surgery for ulcerative colitis. Langen- becks Archiv fur Chirurgie 114:451–454

51. Clausen MR, Tvede M, Mortensen PB (1992) Short- chain fatty acids in pouch contents from patients with and without pouchitis after ileal pouch-anal anastomosis. Gastroenterology 103:1144–1153

52. Penna C, Dozois RR, Tremaine W (1996) Pouchitis after ileal pouch anal anastomosis for chronic ulcerative colitis occur with increased frequency in patients with associated primary sclerosing cholangitis. Gut 38:234–239

53. Teixeira WGJ, Silva JH, Texeira MG (1999) Pouchitis:

extracolonic manifestation of ulcerative colitis? Rev Hosp Clin Fac Med S Paulo 54:155–158

54. Moody GA, Javanthi V, Probert CS et al (1996) Long- term therapy with sulphasalazine protects against colorectal cancer in ulcerative colitis: a retrospective study of colorectal cancer risk and compliance with treatment in Leicestershire. Eur J Gastroenterol Hepa- tol 8:1179–1183

55. Eaden J, Abrams K, Ekbom A et al (2000) Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther 14:145–153