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Colorectal Cancer in Patients with Inflammatory Bowel Disease
Comprehensive
Review
Colorectal Cancer in Patients with Inflammatory Bowel Disease Parsia A. Vagefi, Walter E. Longo Abstract Patients with inflammatory bowel disease (IBD) are subject to increased risks for the development of colorectal cancer (CRC), risks that are attributed to the duration and anatomic extent of disease in patients with ulcerative colitis and Crohn’s disease.Although IBD contributes only 1%-2% to all cases of CRC, the mortality rate in patients with a diagnosis of CRC in the setting of IBD is higher than for those afflicted with sporadic cases of CRC. Given the length of time from IBD onset to the development of CRC, surveillance continues to be widely practiced. Although still under development, novel techniques for the earlier detection of dysplastic lesions have moved to the forefront in an attempt to optimize surveillance strategies and decrease the risk of CRC development. Clinical Colorectal Cancer, Vol. 4, No. 5, 313-319, 2005 Key words: Crohn’s disease, Epithelial dysplasia, Permanent ileostomy, Proctocolectomy, Surgical prophylaxis, Surveillance strategies, Ulcerative colitis
Introduction Inflammatory bowel disease (IBD) comprises 2 major disorders: ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases possess distinct pathologic and clinical characteristics but poorly understood pathogenesis. Ulcerative colitis is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon, which almost invariably involve the rectum and may extend in a continuous fashion to involve other proximal portions of the colon. In contrast, CD is characterized by transmural mucosal inflammation that may involve, in a discontinuous fashion, any component of the entire gastrointestinal tract from the mouth to the perianal area.
Incidence and Prevalence The incidence in the United States of UC is approximately 15 per 100,000 persons, whereas for CD it is approximately 5 per 100,000 persons.1 The prevalence has been estimated to be 200 per 100,000 persons for UC, and 90 per 100,000 persons for CD. Patients with IBD have an increased risk of developing colorectal cancer (CRC) and account for 1%-2% of Department of Surgery, Yale University School of Medicine, New Haven, CT
all cases of CRC in the general population, whereas the majority of cases of CRC are sporadic in origin (65%-85%; Figure 1).2 Colorectal cancer is the most frequent malignant complication in patients with IBD. Indeed, CRC accounts for approximately 15% of all deaths in patients with IBD,2 and the mortality in patients diagnosed with CRC in the setting of IBD is higher than for sporadic CRC.3 Estimates of the risk of CRC in UC, in relation to the onset of disease, have been found to be 2% at 10 years, 8% at 20 years, and 18% at 30 years (irrespective of disease extent), with incidence rates for CRC being higher in the United States and the United Kingdom, as compared with Scandinavia and other countries.4 Although much more is known of the increased risk of CRC associated with UC through referral center and population-based studies,5-8 few populationbased studies have demonstrated increased rates of CRC in patients with CD.9 However, a recent study utilizing a population-based study with the use of a matched non-IBD cohort demonstrated similar increased risks for developing colon carcinoma and hepatobiliary carcinoma among patients with CD and UC.10 This study also demonstrated that patients with UC have an increased risk of developing rectal carcinoma, whereas male patients with CD are at increased risk of developing lymphoma.
Submitted: May 12, 2004; Revised: Jul 29, 2004; Accepted: Aug 3, 2004 Address for correspondence: Walter E. Longo, MD, Yale University School of Medicine, 330 Cedar St, FMB102, New Haven, CT, 06520 Fax: 203-785-2615; e-mail: [email protected]
Pathogenesis The molecular basis for CRC has been described as a multistep process in which the accumulation of multiple discrete
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Inflammatory Bowel Disease and Colon Cancer Figure 1
Prevalence of New Cases of Colorectal Cancer2
Sporadic (~ 75%) Family History (~ 20%) HNPCC (~ 5%) FAP (~ 1%) IBD (~ 1%)
Although accounting for only 1%-2% of all cases of CRC in the general population, patients with IBD have an increased risk of developing CRC. The majority of cases of CRC are sporadic in origin. Abbreviations: FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer
molecular genetic alterations in the colonic epithelial cell leads to the transformation from normal colonic epithelium to an invasive cancer. While the inherited syndromes of CRC rest upon germline mutations, sporadic cancers are thought to result from the accumulation of multiple somatic mutations. There are many specific mutations that can occur in the process of tumorigenesis, including point mutations, altered DNA methylation, gene rearrangements, amplifications, and deletions; however, these mutations can often be classified as to their downstream consequence (gain or loss of function). Some of the more common genetic mutations that have been identified in sporadic CRC include the tumor suppressor genes p53, APC, and DCC, and the oncogene K-ras.11-14 Current CRC surveillance strategies in patients with UC and CD rest on the detection of dysplastic precursor lesions. The dysplasia associated with long-standing colitis shares some of the same molecular alterations responsible for the development of sporadic CRC. However, there are enough differences in the nature of the dysplasia, as well as in the timing and pattern of the molecular alterations that precede tumorigenesis, to consider CRC associated with IBD a unique entity, separate from sporadic CRC, familial adenomatous polyposis, and hereditary nonpolyposis CRC (Figure 2).12 In contrast to the development of sporadic CRC, where the sequential mutation of numerous genes is manifested as the development of adenomatous polyps and then invasive cancer, CRC in the setting of IBD often arises from flat dysplastic tissue. In addition, the neoplasms of colitis-associated CRC are more often multifocal, mucinous, or poorly differentiated than the neoplasms of sporadic CRC. The chronic inflammatory state in IBD most likely creates a different substrate for tumorigenesis than that seen in sporadic CRC.12 Mutations in p53 associated with the carcinogenesis of sporadic CRC usually occur late in the adenoma–carcinoma sequence. In contrast, p53 mutations in colitis-associated CRC occur at an earlier stage of tumorigenesis.12 In addition, whereas abnormalities of the p53 locus are not present in
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nondysplastic mucosa of patients with sporadic CRC, the nondysplastic mucosa in patients with UC has frequently been shown to have aneuploid DNA content, as well as clones of cells with loss of heterozygosity of the p53 gene.12,15 An additional example of a similar genetic alteration, occurring at a different time point in the tumorigenesis of sporadic CRC versus colitis-associated CRC, is loss of APC function. Loss of APC function occurs as an early, often initiating alteration in the development of sporadic colon cancers, followed by subsequent molecular alterations in the adenoma–carcinoma sequence of carcinogenesis. In contrast, loss of APC function is not only much less frequent in the sequence of alterations leading to CRC in a patient with IBD but, if seen, usually occurs late in the molecular pathway of colitis-associated CRC development.12,16 Further research may provide an increased understanding of the sequence and timing of the molecular changes that result in the progression of IBD-associated dysplasia to colonic carcinoma. Although patients with CD are essentially at the same risk of developing CRC as patients with UC, most studies examining the molecular alterations in CRC development from dysplastic tissue have mainly dealt with samples obtained from patients with UC.12 However, the similar rates of CRC among patients with UC and CD suggest a similar tumorigenesis for both diseases.1,17 The median age of CRC diagnosis in CD is 55 years and 43 years in UC, compared with cases of sporadic CRC, whose mean age of onset is 60 years. It has been demonstrated that patients with UC and CD developing CRC share similar clinicopathologic features.11 Colorectal cancer complicating both diseases is observed in similar time frames and has been associated with a long median disease duration (CD, 15 years; UC, 18 years), with the majority of cancers developing after > 8 years of IBD (CD, 75%; UC, 90%). In addition, the detection of multiple carcinomas at the time of diagnosis was equally common (CD, 11%; UC, 12%), with CRC occurring in the area of macroscopic disease in most patients (CD, 85%; UC, 100%) and with dysplasia being present with similar frequency in both diseases (CD, 73%; UC, 79%). Patients with CD-associated colon carcinoma had a 5-year survival rate similar to that of patients with UC-associated colon carcinoma (CD, 46%; UC, 50%).11
Risk The risk of CRC in patients with UC has been suggested to be associated with the extent and duration of disease.18 Patients with pancolitis, classified as extension of disease beyond the hepatic flexure and affecting 10% of patients with UC, have been shown to be at greatest risk for developing CRC, with a 19-fold increase in risk.5 In comparison, patients with UC with left-sided colitis (confined to involving the colon distal to the splenic flexure) have exhibited only a 4-fold increase in risk for the development of CRC. Whereas the risk for CRC development begins to increase 810 years following the onset of symptoms in patients with pancolitis, the risk in patients with left-sided colitis increases 15-20 years following the onset of symptoms.19 Patients
Parsia A. Vagefi, Walter E. Longo presenting with ulcerative proctitis (25% of patients with UC) have not been demonstrated to be at increased risk for CRC.20 Two independent risk factors—backwash ileitis and primary sclerosing cholangitis (PSC)—have been identified as contributing to the development of CRC in patients with UC. In a study of patients with UC undergoing surveillance, patients with backwash ileitis (in which an incompetent ileocecal valve allows for reflux from the diseased colon into the terminal ileum) were found to be ≤ 19 times more likely to develop CRC compared with patients with colitis limited to the left colon or those with pancolitis in the absence of backwash ileitis.21 An additional independent risk factor for the development of CRC in patients with UC is a concurrent diagnosis of PSC.22-24 Patients with UC and PSC have a significantly higher risk for the development of CRC than patients with UC alone. In a 20-year colonoscopic surveillance study, 63% of patients with UC and PSC developed colorectal dysplasia or cancer, in contrast with 30% of patients with UC alone.23 A metaanalysis of 11 studies demonstrated that the risk of CRC development was approximately 4-fold higher in patients with PSC and UC, compared with those with UC alone.24 The development of colorectal dysplasia or cancer in patients with UC and PSC has been noted to distribute to the proximal part of the colon, suggesting an influence of toxic bile in the tumorigenesis.23 Although there is an increased risk of developing CRC for patients with CD, a risk similar in degree to that seen in patients with UC, the absolute number that actually develops CRC remains small. This has been attributed to early colectomy in patients with CD performed to relieve persistent symptoms of extensive colonic disease that where unresponsive to medical treatment.25 The risk of CRC development in patients with CD, much like that seen in patients with UC, has been associated with the extent of colonic disease, as those patients with extensive colitis are at the greatest risk for developing CRC.9 In addition, it has been demonstrated that patients in whom CD with colonic involvement was diagnosed before 30 years of age had a greater relative risk of developing CRC than did those diagnosed at older ages.
Prevention Surgical Prophylaxis Used in combination with rigid surveillance with colonoscopic biopsies for colonic dysplastic changes, surgical prophylaxis has remained a mainstay for physicians attempting to reduce the risk of CRC development in patients with UC. The examination of referral patterns for the surgical management of patients with UC has demonstrated that patients are being referred for operation at earlier time points in their disease, before the onset of catastrophic complications (massive hemorrhage, perforation, fulminant colitis, and acute colonic obstruction) that would necessitate emergency operative intervention.26 Although advances in medical therapy may have reduced the need for emergency surgery for complications of UC, the changes in the referral patterns for operative management may be due to advances in surgical techniques that minimize the physical and mental sequelae of surgery. The devel-
Figure 2
Molecular Pathways in the Development of Colonic Carcinoma2 Sporadic Colon Cancer APC
p53
Normal mucosa
Carcinoma
Adenoma
IBD-Associated Colon Cancer p53 Nondysplastic mucosa
APC Dysplasia
Carcinoma
Schematic representation of the sequence of genetic alterations in the molecular pathways leading to the development of sporadic colonic carcinoma and IBD-associated colonic carcinoma.
opment of continence-preserving procedures, such as the ileal pouch anal canal anastomosis (IPAA) following colectomy and mucosal proctectomy, may make surgery a more attractive option to patients whose colitis has been intractable to medical therapy. Four additional procedures that can be performed in single or multiple stages for patients with UC referred for elective colectomy include proctocolectomy with permanent ileostomy (Brooke ileostomy), proctocolectomy with continent ileostomy (Kock pouch), abdominal colectomy with ileorectal anastomosis, and stapled ileal pouch distal rectal anastomosis following colectomy.27 Continuing advances in laparoscopic surgery may result in the development of more feasible, safe, and effective procedures for the operative management of IBD. Compared with conventional surgery for IBD, a laparoscopic approach has the potential of reducing the length of hospital stay and the amount of hospital charges, decreasing the occurrence of prolonged postoperative ileus and pain, and minimizing the psychologic discomfort associated with large postoperative scars.28,29 Each surgical technique has its own advantages and attendant complications. Therefore, the decision as to when to operate and which operation to choose depends on multiple factors but is not limited to the surgeon’s expertise, clinical setting, or careful patient selection (the patient's age, previous intestinal or anal surgery, obesity, occupation). Thus, the decision to operate should be a discussion between the surgeon and the patient, and should not only meet the patient’s wishes to improve quality of life and reduce the risk of CRC but should also seem to the surgeon to be soundly based. Although surgical prophylaxis can nearly eliminate the risk of CRC development in patients with UC, the procedure has the potential for subsequent complications such as incontinence, fistulas, strictures, pouchitis (50% of patients within 15 years following surgery), pouch failure requiring proximal diversion or end ileostomy (5% of patients following IPAA), and a small potential risk of developing CRC in the remnant rectal cuff following ileoanal pouch anastomosis.30,31
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Inflammatory Bowel Disease and Colon Cancer As previously mentioned, the absolute number of patients with CD who actually develop CRC remains small, usually because early colectomy is performed to relieve persistent symptoms of colonic disease unresponsive to medical treatment.25 As CD can potentially involve the entire gastrointestinal tract and is a chronic, diffuse, recurring disease, it is often not curable by surgery.32 Surgery should be reserved for those patients in whom a complication develops (obstruction or intestinal perforation) or who have symptoms refractory to medical therapy. Given the segmental nature of CD, total colectomy is rarely indicated, as patients will often undergo limited resection of the involved colonic segments.
reports of its application in patients with UC without PSC. The chemoprotective effect of calcium supplementation remains uncertain. Although it has been proposed that calcium supplementation can protect against bile acid–induced colonic tumorigenesis by serving to bind to bile acids in the bowel lumen,33,41 a randomized, double-blind, placebo-controlled clinical trial in patients with UC demonstrated that 2 grams of daily calcium allowed for only an insignificant decrease in the proliferation rate in colon crypts when compared with controls.33,42 Thus, further studies on the antineoplastic role of calcium supplementation in the chemoprevention of CRC in patients with IBD are warranted.
Pharmacotherapy
Surveillance
Although there are no prospective, randomized trials that demonstrate a clear beneficial effect of pharmacotherapy on preventing the development of CRC in the setting of IBD, there is preliminary evidence that supports the protective effect of a few agents.33 It has been demonstrated that the regular use of nonsteroidal antiinflammatory drugs (NSAID) is associated with an overall significant risk reduction of sporadic CRC in men and in women.34 Sulfasalazine becomes an NSAID that has been used for induction and maintenance therapy in patients with UC. Following administration, sulfasalazine is separated into sulfapyridine (which possesses bacteriostatic properties) and 5-ASA (which possesses antiinflammatory properties). There are data that support the use of 5-ASA agents in order to decrease rates of dysplasia and CRC.34 Although steroids possess robust antiinflammatory properties and thus may play a significant antineoplastic role, the adverse side effects associated with their long-term application prevents their use as safe chemopreventive agents.33 Folate has been shown to have a protective role against neoplastic progression, and, in fact, epidemiologic studies have demonstrated that increased dietary folate intake is associated with a decreased prevalence of CRC.35 Additional evidence in the literature has demonstrated that increasing the dietary intake of folate could inhibit the development of colorectal adenomas.36 In addition, folate deficiency may serve as a risk factor for the development of a neoplastic process. Studies have yet to be performed demonstrating a beneficial effect for increased folate intake in the development of CRC in patients with IBD. However, given the safety of chronic folate use, its ease of administration, low cost, and potential to be protective against colonic neoplasia, folate supplementation should be offered to all patients with UC.33 Initial in vitro and rodent studies have suggested that the synthetic bile acid-ursodeoxycholic acid (ursodiol) may play a chemoprotective role against development of colon cancer.37-39 Subsequently, ursodiol has been shown to decrease the risk of colonic dysplasia in patients with UC with PSC in a retrospective case-control study,41 as well as in a randomized placebocontrolled trial.42 The latter study was associated with a significant decrease in risk for developing colorectal dysplasia or cancer in patients with UC and PSC. Thus, ursodiol use should be considered in patients with UC and PSC; however, there are no
The rationale for surveillance in patients with CD or UC is based on the premise that CRC in patients with IBD is preceded by detectable dysplastic changes within the colonic epithelium. A dysplastic epithelium may serve as a marker for coexisting malignancy; in addition, the detection and removal of a preneoplastic or neoplastic lesion would cure or reduce mortality in patients with IBD and CRC. Thus, colonoscopy with biopsies has remained one of the main modalities in CRC surveillance for patients with IBD. A standardized classification for the interpretation of epithelial dysplasia in ulcerative colitis was developed in 1983.43 Although the predictive value of dysplasia has been best studied in UC, the association between dysplasia and CRC in CD appears to be similar to that in UC, thus the classification system of the epithelial changes was proposed to be applicable to other forms of IBD as well. The term dysplasia was reserved for epithelial changes that were deemed to be unequivocally neoplastic and would thus progress directly to invasive carcinoma, but were confined to the lining epithelial cells without penetration into the lamina propria. The classification system categorized histology from biopsy specimens as negative, indefinite, or positive for dysplasia. The negative category included the detection of inflammatory and regenerative lesions, and the suggested patient management consisted of only continued regular surveillance. The indefinite category was applied to specimens in which the epithelial changes exceeded the limits of ordinary regeneration but were insufficient for an unequivocal diagnosis of dysplasia. The subgroups of the indefinite category were probably negative, unknown, and probably positive, and the suggestions for patient management included early repeat biopsy to assess the indefinite changes more accurately. The positive category was divided into 2 subcategories: (1) high-grade dysplasia, for which the suggestion for patient management was strong consideration for colectomy following confirmation of the diagnosis, and (2) low-grade dysplasia, for which the suggestion for patient management consisted of confirmation and early repeat biopsy or colectomy.43 Dysplastic areas may appear flat or only slightly elevated above the level of the mucosa, or they may occur within or near a lesion or mass. The latter are referred to as a dysplasiaassociated lesion or mass (DALM) and have been highly as-
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Parsia A. Vagefi, Walter E. Longo sociated with the presence of invasive colorectal cancer.44-46 Indeed, detection of a DALM has often been considered justification for colectomy. As the risk for sporadic adenomas in patients with IBD is similar to that of the general population, sporadic adenomas must be distinguished from a DALM in order to prevent unnecessary colectomy. Two molecular markers have been proposed for distinguishing DALM from sporadic adenomas: β-catenin (a cell membrane protein) and p53 (a tumor suppressor gene). In a comparison of DALM specimens with sporadic adenomas it was demonstrated that positive staining for β-catenin was more common in sporadic adenomas than in DALM (40% vs. 8%), whereas positive staining for p53 was more common in DALM than in sporadic adenomas (29% vs. 5%).47
Colonoscopic Surveillance As with the finding of a DALM, there is a general consensus that the finding of high-grade dysplasia during colonoscopic surveillance warrants prompt colectomy, because patients with high-grade dysplasia have a 30%-40% risk of concurrent or imminent CRC.43,46 However, there is less agreement regarding the optimal strategy for the management of low-grade dysplasia detected upon colonoscopic surveillance, as its predictive value for progression to high-grade dysplasia or neoplasia has remained unclear.48 Thus, the outcome following the detection of a low-grade dysplastic lesion has been early colectomy or continued surveillance, depending on the practitioner. However, a recent retrospective study, albeit with a limited sample size, has demonstrated that a finding of flat low-grade dysplasia during surveillance in patients with UC is a strong predictor of progression to advanced neoplasia (high-grade dysplasia or CRC) and that early colectomy should be recommended for such patients.50 This study, which included 46 patients with UC and the detection of lowgrade dysplasia, demonstrated a rate of progression to highgrade dysplasia or CRC of 53% at 5 years in those patients who continued in the surveillance program. Of the 11 patients who underwent colectomy within 6 months of the diagnosis of low-grade dysplasia, 18% had CRC, all of which were stage I. In contrast, 20% of the 35 patients who elected not to undergo immediate colectomy, but continued surveillance, were diagnosed with CRC, which included stage II (40% of those diagnosed) and stage III (60% of those diagnosed) neoplasms. Importantly, the authors noted that the natural history of low-grade dysplastic lesions, in terms of the potential for regression or the step-wise progression to high-grade dysplasia and then CRC, remains controversial.48 Attempting to balance the risk of CRC development in a patient with IBD, versus the short- and long-term morbidity and mortality from surgery, will challenge the most experienced of practitioners. Although the data for risk reduction of CRC mortality by immediate colectomy for patients with low-grade dysplasia continue to deserve investigation, there is growing evidence that immediate colectomy may result in better survival than implementation of continued surveillance in patients with lowgrade dysplasia.
Observational evidence has suggested the potential benefit for colonoscopic surveillance in patients with chronic extensive colitis in order to identify patients with dysplasia and thus prevent malignant transformation; however, there remains an absence of published randomized controlled trials or epidemiologic studies that demonstrate a reduction in the mortality rate of CRC in patients with IBD following the implementation of a colonoscopic surveillance program.49 The goal of colonoscopic surveillance programs has been the early detection of dysplasia, as patients diagnosed with CRC after the onset of symptoms (ie, abdominal pain or bleeding) have been shown to have a worse prognosis than those detected during surveillance.50 Although surveillance colonoscopy has gained wide acceptance among practitioners, the optimal surveillance strategy for CRC in patients with IBD has yet to be established. Therefore, multiple recommendations have been issued by major societies, including the American Gastroenterological Association, the American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, and the British Society of Gastroenterology. It is the opinion of the authors, based upon best-practice patterns, that patients with ulcerative pancolitis or Crohn’s colitis who are surgical candidates should undergo surveillance colonoscopy after 8 years of disease, followed by annual colonoscopic examinations. Four biopsies should be obtained every 10 cm from the cecum to the rectum, and, in addition, any suspicious lesions or masses should be biopsied. Patients with left-sided UC should begin colonoscopic evaluations after 15 years of disease and then followed by annual colonoscopic examinations. Surveillance for patients with ulcerative proctitis is not recommended. Colectomy should be recommended for patients who are found to have high-grade dysplasia, lowgrade dysplasia, or a DALM, assuming the DALM has been distinguished from a sporadic adenoma. Based upon the inherent limitations of colonoscopic surveillance with random biopsies for the detection of dysplastic changes, practitioners have begun to investigate newer techniques that could assist in the detection of dysplasia or cancer. Although certain novel techniques are in their infancy, their potential for earlier and more accurate detection of dysplasia in surveillance programs for patients with IBD warrants their being mentioned. Sialosyl-Tn is a mucin-associated carbohydrate antigen whose expression in nondysplastic colonic mucosa may precede the development of neoplasia in patients with long-standing UC.51 Immunohistochemical staining directed for this cell surface marker may serve as a useful adjunct to colonoscopic surveillance with random biopsies. The detection of allelic deletions and point mutations of tumor suppressor genes (such as p53, Rb, mcc, and APC) may also provide for improved surveillance, as these genes may be involved in the tumorigenesis of CRC in patients with IBD.52 Advances in flow cytometric analysis for the detection of DNA aneuploidy in mucosal specimens of patients with UC may improve the utility of colorectal surveillance, as it has been shown that changes in nuclear DNA
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Inflammatory Bowel Disease and Colon Cancer content appear to precede dysplasia in the malignant transformation of colonic mucosa in UC.53
Chromoendoscopy Chromoendoscopy involves the topical application of stains or pigments to assist in tissue localization, characterization, or diagnosis during gastrointestinal endoscopy.54 The staining of the gastrointestinal mucosa further defines the mucosal surface and, when used in conjunction with magnifying colonoscopy, may assist in the detection of mucosal alterations and allow for more targeted biopsies of the colonic epithelium. A recent randomized, controlled trial demonstrated that colonic mucosal staining with methylene blue enhanced the ability to delineate the extent of inflammatory changes by an average of 14 cm. In addition, and more important, the chromoendoscopy identified significantly more neoplastic lesions, in comparison with routine surveillance colonoscopy with random biopsy in patients with UC.55 The chromoendoscopy was performed by spraying the colonic mucosa with methylene blue 0.1% in 30-cm segments. The mucosa was then examined with a magnifying endoscope, and, as the uptake of dye in the neoplastic epithelium is poor, biopsies were directed to the paler, less blue, or white areas.
Adjuvant Therapy Relapse for patients who have undergone potentially curative colonic resections is thought to surface from clinically silent micrometastases present at the time of operation. Thus, the goal of postoperative adjuvant therapy has been to decrease the recurrence rate following curative resection by eradicating micrometastases, thus enhancing rates of survival. Although most of the literature concerning adjuvant systemic chemotherapy for colonic cancer is based on data from the non-IBD population, the advantages of adjuvant therapy are likely applicable to both populations with colon cancer. Much like patients with sporadic colon cancer, survival in patients with IBD who develop colon cancer has been shown to be stage dependent.56 Currently, the available data support the routine use of adjuvant 5-fluorouracil (5-FU)–based systemic therapy in patients with stage III disease following resection. The use of adjuvant therapy in this setting has demonstrated reduction in the risk of recurrence and death from colon cancer.57 In contrast, the use of adjuvant chemotherapy in patients with stage II disease remains a controversial topic and is currently being considered for patients with high-risk stage II disease. This includes patients with obstruction, perforation, T4 lesions, or T3 lesions with a depth of invasion > 15 mm beyond the outer border of the muscularis propria.58 The improvement in reduction of stage III mortality with combination 5-FU/leucovorin (LV), as opposed to 5-FU/levamisole, has allowed 5-FU/LV to remain the standard of care in the adjuvant treatment of colon cancer. However, the arsenal of adjuvant chemotherapy for colon cancer is rapidly expanding, as recent data from the MOSAIC trial have demonstrated that the combination of oxaliplatin with 5-FU/LV
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(FOLFOX) is superior in 3-year disease-free survival compared with 5-FU/LV in the adjuvant treatment of colon cancer.59 Investigations into the use of irinotecan combined with FOLFIRI (infusional 5-FU/LV), as well as the use of monoclonal antibodies bevacizumab (antivascular endothelial growth factor) and cetuximab (antiepidermal growth factor receptor) in the treatment of colonic carcinoma, are also under way.60 These recent and dramatic advances in adjuvant chemotherapy for colon cancer hold promise to reduce mortality from colonic carcinoma following surgical curative resection in the IBD and non-IBD populations.
Conclusion Although only a small portion of the total number of cases of CRC, the development of a colonic neoplasm remains the most frequent malignant complication in patients with IBD and accounts for 15% of all deaths in patients with IBD. Since the first description of the association between UC and CRC in 192561 and subsequent descriptions of the similar risk of CRC in CD,17 practitioners have sought to further delineate the process by which the colonic epithelium in patients with IBD undergoes tumorigenesis. Although surgery remains a mainstay in the prevention and treatment of CRC in the patient with IBD, ongoing investigations into the treatment of IBD and the prevention and earlier detection of dysplastic changes within the colonic epithelium may produce significant reductions in the risk of development of CRC.
References
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Parsia A. Vagefi, Walter E. Longo nesis. Cell 1990; 61:759. 14. Lynch JP, Hoops TC. The genetic pathogenesis of colorectal cancer. Hematol Oncol Clin North Am 2002; 16:775-810. 15. Burmer GC, Rabinovitch PS, Haggitt RC, et al. Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology 1992; 103:1602-1610. 16. Tarmin L, Yin J, Harpaz N, et al. Adenomatous polyposis coli gene mutations in ulcerative colitis-associated dysplasias and cancers versus sporadic colon neoplasms. Cancer Res 1995; 55:2035-2038. 17. Sachar DB. Cancer in Crohn’s disease: dispelling the myths. Gut 1994; 35:1507-1508 18. MacDougall IP. The cancer risk in ulcerative colitis. Lancet 1964; 2:655. 19. Greenstein AJ, Sachar DB, Smith H, et al. Cancer in universal and left-sided ulcerative colitis: factors determining risk. Gastroenterology1979; 77:290-294. 20. Levin B. Inflammatory bowel disease and colon cancer. Cancer 1992; 70(5 suppl):1313-3136. 21. Heuschen UA, Hinz U, Allemeyer EH, et al. Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology 2001; 120:841-847. 22. 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 23. Lindberg BU, Broome U, Persson B. Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum 2001; 44:77-85. 24. Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002; 56:48-54. 25. Gillen CD, Walmsley RS, Prior P, et al. Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994; 35:1590-1592. 26. Goudet P, Dozois RR, Kelly KA, et al. Changing referral patterns for surgical treatment of ulcerative colitis. Mayo Clin Proc 1996; 71:743-747. 27. Hulten L, Proctocolectomy and ileostomy to pouch surgery for ulcerative colitis. World J Surg 1998; 22:335-341. 28. Shore G, Gonzalez QH, Bondora A, et al. Laparoscopic versus conventional ileocolectomy for primary Crohn disease. Arch Surg 2003;138:76-79. 29. Santoro E, Carlini M, Carboni F, et al. Laparoscopic total proctocolectomy with ileal J pouch-anal anastomosis. Hepatogastroenterology 1999; 46:894-899. 30. Marcello PW, Roberts PL, Schoetz DJ Jr, et al. Long-term results of the ileoanal pouch procedure. Arch Surg 1993; 128:500-503. 31. Stein RB, Lichtenstein GR. Complications after ileal pouch-anal anastomosis. Semin Gastrointest Dis 2000; 11:2-9. 32. Shivananda S, Hordijk ML, Pena AS, et al. Crohn’s disease: risk of recurrence and reoperation in a defined population. Gut 1989; 30:990-995. 33. Croog VJ, Ullman TA, Itzkowitz SH. Chemoprevention of colorectal cancer in ulcerative colitis. Int J Colorectal Dis 2003; 18:392-400. 34. Muscat JE, Stellman SD, Wynder EL. Nonsteroidal antiinflammatory drugs and colorectal cancer. Cancer 1994; 74:1847-1854. 35. Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991; 20:368-374 36. Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993; 85:875-884 37. Earnest DL, Holubec H, Wali RK, et al. Chemoprevention of azoxymethane-induced colonic carcinogenesis by supplemental dietary ursodeoxycholic acid. Cancer Res 1994; 54:5071-5074. 38. Narisawa T, Fukaura Y, Terada K, et al. Prevention of N-methylnitrosourea-induced colon tumorigenesis by ursodeoxycholic acid in F344 rats. Jpn J Cancer Res 1998; 89:1009-1013.
39. Tung BY, Emond MJ, Haggitt RC, et al. 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. 40. Pardi DS, Loftus EV Jr, Kremers WK, et al. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003; 124:889-893. 41. Newmarck H, Wargovich M, Bruce W. Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst 1984; 72:1323-1325. 42. Bostick RM, Boldt M, Darif M, et al. Calcium and colorectal epithelial cell proliferation in ulcerative colitis. Cancer Epidemiol Biomarkers Prev 1997; 6:1021-1027. 43. Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983; 14:931-68. 44. Blackstone MO, Riddell RH, Rogers GBH, et al. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in longstanding ulcerative colitis: an indication for colectomy. Gastroenterology 1981; 80:366-374. 45. Bernstein CN. ALMs versus DALMs in ulcerative colitis: polypectomy or colectomy? Gastroenterology 1999; 117:1488-1492. 46. Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994; 343:71-74. 47. Walsh SV, Loda M, Torres CM, et al. P53 and beta catenin expression in chronic ulcerative colitis--associated polypoid dysplasia and sporadic adenomas: an immunohistochemical study. Am J Surg Pathol 1999; 23:963-969. 48. Ullman T, Croog V, Harpaz N, et al. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003; 125:1311-1319. 49. Karlen P, Kornfeld D, Brostrom O, et al. Is colonoscopic surveillance reducing colorectal cancer mortality in ulcerative colitis? A population based case control study. Gut 1998; 42:711-714. 50. Choi PM, Nugent FW, Schoetz DJ Jr, et al. Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis. Gastroenterology 1993; 105:418-424. 51. Itzkowitz SH, Young E, Dubois D, et al. Sialosyl-Tn antigen is prevalent and precedes dysplasia in ulcerative colitis: a retrospective case-control study. Gastroenterology 1996; 110:694-704. 52. Greenwald BD, Harpaz N, Yin J, et al. Loss of heterozygosity affecting the p53, Rb, and mcc/apc tumor suppressor gene loci in dysplastic and cancerous ulcerative colitis. Cancer Res 1992; 52:741-745. 53. Lofberg R, Brostrom O, Karlen P, et al. DNA aneuploidy in ulcerative colitis: reproducibility, topographic distribution, and relation to dysplasia. Gastroenterology 1992; 102:1149-1154. 54. Fennerty MB. Tissue staining. Gastrointest Endosc Clin N Am 1994; 4:297-311. 55. Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003; 124:880888. 56. Connell WR, Talbot IC, Harpaz N, et al. Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis. Gut 1994; 35:1419-1423. 57. Moore HC, Haller DG. Adjuvant therapy of colon cancer. Semin Oncol 1999; 26:545-555. 58. Merkel S, Wein A, Gunther K, et al. High-risk groups of patients with stage II colon carcinoma. Cancer 2001; 92:1435-1443. 59. Andre T, Boni C, Mounedji-Boudiaf L, et al. Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343-2351. 60. O’Connell MJ. Current status of adjuvant therapy for colorectal cancer. Oncology (Huntingt) 2004; 18:751-755. 61. Crohn BB, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis. Am J Med Sci 1925; 170:220-228.
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Review
Colorectal Cancer in Patients with Inflammatory Bowel Disease Parsia A. Vagefi, Walter E. Longo Abstract Patients with inflammatory bowel disease (IBD) are subject to increased risks for the development of colorectal cancer (CRC), risks that are attributed to the duration and anatomic extent of disease in patients with ulcerative colitis and Crohn’s disease.Although IBD contributes only 1%-2% to all cases of CRC, the mortality rate in patients with a diagnosis of CRC in the setting of IBD is higher than for those afflicted with sporadic cases of CRC. Given the length of time from IBD onset to the development of CRC, surveillance continues to be widely practiced. Although still under development, novel techniques for the earlier detection of dysplastic lesions have moved to the forefront in an attempt to optimize surveillance strategies and decrease the risk of CRC development. Clinical Colorectal Cancer, Vol. 4, No. 5, 313-319, 2005 Key words: Crohn’s disease, Epithelial dysplasia, Permanent ileostomy, Proctocolectomy, Surgical prophylaxis, Surveillance strategies, Ulcerative colitis
Introduction Inflammatory bowel disease (IBD) comprises 2 major disorders: ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases possess distinct pathologic and clinical characteristics but poorly understood pathogenesis. Ulcerative colitis is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon, which almost invariably involve the rectum and may extend in a continuous fashion to involve other proximal portions of the colon. In contrast, CD is characterized by transmural mucosal inflammation that may involve, in a discontinuous fashion, any component of the entire gastrointestinal tract from the mouth to the perianal area.
Incidence and Prevalence The incidence in the United States of UC is approximately 15 per 100,000 persons, whereas for CD it is approximately 5 per 100,000 persons.1 The prevalence has been estimated to be 200 per 100,000 persons for UC, and 90 per 100,000 persons for CD. Patients with IBD have an increased risk of developing colorectal cancer (CRC) and account for 1%-2% of Department of Surgery, Yale University School of Medicine, New Haven, CT
all cases of CRC in the general population, whereas the majority of cases of CRC are sporadic in origin (65%-85%; Figure 1).2 Colorectal cancer is the most frequent malignant complication in patients with IBD. Indeed, CRC accounts for approximately 15% of all deaths in patients with IBD,2 and the mortality in patients diagnosed with CRC in the setting of IBD is higher than for sporadic CRC.3 Estimates of the risk of CRC in UC, in relation to the onset of disease, have been found to be 2% at 10 years, 8% at 20 years, and 18% at 30 years (irrespective of disease extent), with incidence rates for CRC being higher in the United States and the United Kingdom, as compared with Scandinavia and other countries.4 Although much more is known of the increased risk of CRC associated with UC through referral center and population-based studies,5-8 few populationbased studies have demonstrated increased rates of CRC in patients with CD.9 However, a recent study utilizing a population-based study with the use of a matched non-IBD cohort demonstrated similar increased risks for developing colon carcinoma and hepatobiliary carcinoma among patients with CD and UC.10 This study also demonstrated that patients with UC have an increased risk of developing rectal carcinoma, whereas male patients with CD are at increased risk of developing lymphoma.
Submitted: May 12, 2004; Revised: Jul 29, 2004; Accepted: Aug 3, 2004 Address for correspondence: Walter E. Longo, MD, Yale University School of Medicine, 330 Cedar St, FMB102, New Haven, CT, 06520 Fax: 203-785-2615; e-mail: [email protected]
Pathogenesis The molecular basis for CRC has been described as a multistep process in which the accumulation of multiple discrete
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Inflammatory Bowel Disease and Colon Cancer Figure 1
Prevalence of New Cases of Colorectal Cancer2
Sporadic (~ 75%) Family History (~ 20%) HNPCC (~ 5%) FAP (~ 1%) IBD (~ 1%)
Although accounting for only 1%-2% of all cases of CRC in the general population, patients with IBD have an increased risk of developing CRC. The majority of cases of CRC are sporadic in origin. Abbreviations: FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer
molecular genetic alterations in the colonic epithelial cell leads to the transformation from normal colonic epithelium to an invasive cancer. While the inherited syndromes of CRC rest upon germline mutations, sporadic cancers are thought to result from the accumulation of multiple somatic mutations. There are many specific mutations that can occur in the process of tumorigenesis, including point mutations, altered DNA methylation, gene rearrangements, amplifications, and deletions; however, these mutations can often be classified as to their downstream consequence (gain or loss of function). Some of the more common genetic mutations that have been identified in sporadic CRC include the tumor suppressor genes p53, APC, and DCC, and the oncogene K-ras.11-14 Current CRC surveillance strategies in patients with UC and CD rest on the detection of dysplastic precursor lesions. The dysplasia associated with long-standing colitis shares some of the same molecular alterations responsible for the development of sporadic CRC. However, there are enough differences in the nature of the dysplasia, as well as in the timing and pattern of the molecular alterations that precede tumorigenesis, to consider CRC associated with IBD a unique entity, separate from sporadic CRC, familial adenomatous polyposis, and hereditary nonpolyposis CRC (Figure 2).12 In contrast to the development of sporadic CRC, where the sequential mutation of numerous genes is manifested as the development of adenomatous polyps and then invasive cancer, CRC in the setting of IBD often arises from flat dysplastic tissue. In addition, the neoplasms of colitis-associated CRC are more often multifocal, mucinous, or poorly differentiated than the neoplasms of sporadic CRC. The chronic inflammatory state in IBD most likely creates a different substrate for tumorigenesis than that seen in sporadic CRC.12 Mutations in p53 associated with the carcinogenesis of sporadic CRC usually occur late in the adenoma–carcinoma sequence. In contrast, p53 mutations in colitis-associated CRC occur at an earlier stage of tumorigenesis.12 In addition, whereas abnormalities of the p53 locus are not present in
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nondysplastic mucosa of patients with sporadic CRC, the nondysplastic mucosa in patients with UC has frequently been shown to have aneuploid DNA content, as well as clones of cells with loss of heterozygosity of the p53 gene.12,15 An additional example of a similar genetic alteration, occurring at a different time point in the tumorigenesis of sporadic CRC versus colitis-associated CRC, is loss of APC function. Loss of APC function occurs as an early, often initiating alteration in the development of sporadic colon cancers, followed by subsequent molecular alterations in the adenoma–carcinoma sequence of carcinogenesis. In contrast, loss of APC function is not only much less frequent in the sequence of alterations leading to CRC in a patient with IBD but, if seen, usually occurs late in the molecular pathway of colitis-associated CRC development.12,16 Further research may provide an increased understanding of the sequence and timing of the molecular changes that result in the progression of IBD-associated dysplasia to colonic carcinoma. Although patients with CD are essentially at the same risk of developing CRC as patients with UC, most studies examining the molecular alterations in CRC development from dysplastic tissue have mainly dealt with samples obtained from patients with UC.12 However, the similar rates of CRC among patients with UC and CD suggest a similar tumorigenesis for both diseases.1,17 The median age of CRC diagnosis in CD is 55 years and 43 years in UC, compared with cases of sporadic CRC, whose mean age of onset is 60 years. It has been demonstrated that patients with UC and CD developing CRC share similar clinicopathologic features.11 Colorectal cancer complicating both diseases is observed in similar time frames and has been associated with a long median disease duration (CD, 15 years; UC, 18 years), with the majority of cancers developing after > 8 years of IBD (CD, 75%; UC, 90%). In addition, the detection of multiple carcinomas at the time of diagnosis was equally common (CD, 11%; UC, 12%), with CRC occurring in the area of macroscopic disease in most patients (CD, 85%; UC, 100%) and with dysplasia being present with similar frequency in both diseases (CD, 73%; UC, 79%). Patients with CD-associated colon carcinoma had a 5-year survival rate similar to that of patients with UC-associated colon carcinoma (CD, 46%; UC, 50%).11
Risk The risk of CRC in patients with UC has been suggested to be associated with the extent and duration of disease.18 Patients with pancolitis, classified as extension of disease beyond the hepatic flexure and affecting 10% of patients with UC, have been shown to be at greatest risk for developing CRC, with a 19-fold increase in risk.5 In comparison, patients with UC with left-sided colitis (confined to involving the colon distal to the splenic flexure) have exhibited only a 4-fold increase in risk for the development of CRC. Whereas the risk for CRC development begins to increase 810 years following the onset of symptoms in patients with pancolitis, the risk in patients with left-sided colitis increases 15-20 years following the onset of symptoms.19 Patients
Parsia A. Vagefi, Walter E. Longo presenting with ulcerative proctitis (25% of patients with UC) have not been demonstrated to be at increased risk for CRC.20 Two independent risk factors—backwash ileitis and primary sclerosing cholangitis (PSC)—have been identified as contributing to the development of CRC in patients with UC. In a study of patients with UC undergoing surveillance, patients with backwash ileitis (in which an incompetent ileocecal valve allows for reflux from the diseased colon into the terminal ileum) were found to be ≤ 19 times more likely to develop CRC compared with patients with colitis limited to the left colon or those with pancolitis in the absence of backwash ileitis.21 An additional independent risk factor for the development of CRC in patients with UC is a concurrent diagnosis of PSC.22-24 Patients with UC and PSC have a significantly higher risk for the development of CRC than patients with UC alone. In a 20-year colonoscopic surveillance study, 63% of patients with UC and PSC developed colorectal dysplasia or cancer, in contrast with 30% of patients with UC alone.23 A metaanalysis of 11 studies demonstrated that the risk of CRC development was approximately 4-fold higher in patients with PSC and UC, compared with those with UC alone.24 The development of colorectal dysplasia or cancer in patients with UC and PSC has been noted to distribute to the proximal part of the colon, suggesting an influence of toxic bile in the tumorigenesis.23 Although there is an increased risk of developing CRC for patients with CD, a risk similar in degree to that seen in patients with UC, the absolute number that actually develops CRC remains small. This has been attributed to early colectomy in patients with CD performed to relieve persistent symptoms of extensive colonic disease that where unresponsive to medical treatment.25 The risk of CRC development in patients with CD, much like that seen in patients with UC, has been associated with the extent of colonic disease, as those patients with extensive colitis are at the greatest risk for developing CRC.9 In addition, it has been demonstrated that patients in whom CD with colonic involvement was diagnosed before 30 years of age had a greater relative risk of developing CRC than did those diagnosed at older ages.
Prevention Surgical Prophylaxis Used in combination with rigid surveillance with colonoscopic biopsies for colonic dysplastic changes, surgical prophylaxis has remained a mainstay for physicians attempting to reduce the risk of CRC development in patients with UC. The examination of referral patterns for the surgical management of patients with UC has demonstrated that patients are being referred for operation at earlier time points in their disease, before the onset of catastrophic complications (massive hemorrhage, perforation, fulminant colitis, and acute colonic obstruction) that would necessitate emergency operative intervention.26 Although advances in medical therapy may have reduced the need for emergency surgery for complications of UC, the changes in the referral patterns for operative management may be due to advances in surgical techniques that minimize the physical and mental sequelae of surgery. The devel-
Figure 2
Molecular Pathways in the Development of Colonic Carcinoma2 Sporadic Colon Cancer APC
p53
Normal mucosa
Carcinoma
Adenoma
IBD-Associated Colon Cancer p53 Nondysplastic mucosa
APC Dysplasia
Carcinoma
Schematic representation of the sequence of genetic alterations in the molecular pathways leading to the development of sporadic colonic carcinoma and IBD-associated colonic carcinoma.
opment of continence-preserving procedures, such as the ileal pouch anal canal anastomosis (IPAA) following colectomy and mucosal proctectomy, may make surgery a more attractive option to patients whose colitis has been intractable to medical therapy. Four additional procedures that can be performed in single or multiple stages for patients with UC referred for elective colectomy include proctocolectomy with permanent ileostomy (Brooke ileostomy), proctocolectomy with continent ileostomy (Kock pouch), abdominal colectomy with ileorectal anastomosis, and stapled ileal pouch distal rectal anastomosis following colectomy.27 Continuing advances in laparoscopic surgery may result in the development of more feasible, safe, and effective procedures for the operative management of IBD. Compared with conventional surgery for IBD, a laparoscopic approach has the potential of reducing the length of hospital stay and the amount of hospital charges, decreasing the occurrence of prolonged postoperative ileus and pain, and minimizing the psychologic discomfort associated with large postoperative scars.28,29 Each surgical technique has its own advantages and attendant complications. Therefore, the decision as to when to operate and which operation to choose depends on multiple factors but is not limited to the surgeon’s expertise, clinical setting, or careful patient selection (the patient's age, previous intestinal or anal surgery, obesity, occupation). Thus, the decision to operate should be a discussion between the surgeon and the patient, and should not only meet the patient’s wishes to improve quality of life and reduce the risk of CRC but should also seem to the surgeon to be soundly based. Although surgical prophylaxis can nearly eliminate the risk of CRC development in patients with UC, the procedure has the potential for subsequent complications such as incontinence, fistulas, strictures, pouchitis (50% of patients within 15 years following surgery), pouch failure requiring proximal diversion or end ileostomy (5% of patients following IPAA), and a small potential risk of developing CRC in the remnant rectal cuff following ileoanal pouch anastomosis.30,31
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Inflammatory Bowel Disease and Colon Cancer As previously mentioned, the absolute number of patients with CD who actually develop CRC remains small, usually because early colectomy is performed to relieve persistent symptoms of colonic disease unresponsive to medical treatment.25 As CD can potentially involve the entire gastrointestinal tract and is a chronic, diffuse, recurring disease, it is often not curable by surgery.32 Surgery should be reserved for those patients in whom a complication develops (obstruction or intestinal perforation) or who have symptoms refractory to medical therapy. Given the segmental nature of CD, total colectomy is rarely indicated, as patients will often undergo limited resection of the involved colonic segments.
reports of its application in patients with UC without PSC. The chemoprotective effect of calcium supplementation remains uncertain. Although it has been proposed that calcium supplementation can protect against bile acid–induced colonic tumorigenesis by serving to bind to bile acids in the bowel lumen,33,41 a randomized, double-blind, placebo-controlled clinical trial in patients with UC demonstrated that 2 grams of daily calcium allowed for only an insignificant decrease in the proliferation rate in colon crypts when compared with controls.33,42 Thus, further studies on the antineoplastic role of calcium supplementation in the chemoprevention of CRC in patients with IBD are warranted.
Pharmacotherapy
Surveillance
Although there are no prospective, randomized trials that demonstrate a clear beneficial effect of pharmacotherapy on preventing the development of CRC in the setting of IBD, there is preliminary evidence that supports the protective effect of a few agents.33 It has been demonstrated that the regular use of nonsteroidal antiinflammatory drugs (NSAID) is associated with an overall significant risk reduction of sporadic CRC in men and in women.34 Sulfasalazine becomes an NSAID that has been used for induction and maintenance therapy in patients with UC. Following administration, sulfasalazine is separated into sulfapyridine (which possesses bacteriostatic properties) and 5-ASA (which possesses antiinflammatory properties). There are data that support the use of 5-ASA agents in order to decrease rates of dysplasia and CRC.34 Although steroids possess robust antiinflammatory properties and thus may play a significant antineoplastic role, the adverse side effects associated with their long-term application prevents their use as safe chemopreventive agents.33 Folate has been shown to have a protective role against neoplastic progression, and, in fact, epidemiologic studies have demonstrated that increased dietary folate intake is associated with a decreased prevalence of CRC.35 Additional evidence in the literature has demonstrated that increasing the dietary intake of folate could inhibit the development of colorectal adenomas.36 In addition, folate deficiency may serve as a risk factor for the development of a neoplastic process. Studies have yet to be performed demonstrating a beneficial effect for increased folate intake in the development of CRC in patients with IBD. However, given the safety of chronic folate use, its ease of administration, low cost, and potential to be protective against colonic neoplasia, folate supplementation should be offered to all patients with UC.33 Initial in vitro and rodent studies have suggested that the synthetic bile acid-ursodeoxycholic acid (ursodiol) may play a chemoprotective role against development of colon cancer.37-39 Subsequently, ursodiol has been shown to decrease the risk of colonic dysplasia in patients with UC with PSC in a retrospective case-control study,41 as well as in a randomized placebocontrolled trial.42 The latter study was associated with a significant decrease in risk for developing colorectal dysplasia or cancer in patients with UC and PSC. Thus, ursodiol use should be considered in patients with UC and PSC; however, there are no
The rationale for surveillance in patients with CD or UC is based on the premise that CRC in patients with IBD is preceded by detectable dysplastic changes within the colonic epithelium. A dysplastic epithelium may serve as a marker for coexisting malignancy; in addition, the detection and removal of a preneoplastic or neoplastic lesion would cure or reduce mortality in patients with IBD and CRC. Thus, colonoscopy with biopsies has remained one of the main modalities in CRC surveillance for patients with IBD. A standardized classification for the interpretation of epithelial dysplasia in ulcerative colitis was developed in 1983.43 Although the predictive value of dysplasia has been best studied in UC, the association between dysplasia and CRC in CD appears to be similar to that in UC, thus the classification system of the epithelial changes was proposed to be applicable to other forms of IBD as well. The term dysplasia was reserved for epithelial changes that were deemed to be unequivocally neoplastic and would thus progress directly to invasive carcinoma, but were confined to the lining epithelial cells without penetration into the lamina propria. The classification system categorized histology from biopsy specimens as negative, indefinite, or positive for dysplasia. The negative category included the detection of inflammatory and regenerative lesions, and the suggested patient management consisted of only continued regular surveillance. The indefinite category was applied to specimens in which the epithelial changes exceeded the limits of ordinary regeneration but were insufficient for an unequivocal diagnosis of dysplasia. The subgroups of the indefinite category were probably negative, unknown, and probably positive, and the suggestions for patient management included early repeat biopsy to assess the indefinite changes more accurately. The positive category was divided into 2 subcategories: (1) high-grade dysplasia, for which the suggestion for patient management was strong consideration for colectomy following confirmation of the diagnosis, and (2) low-grade dysplasia, for which the suggestion for patient management consisted of confirmation and early repeat biopsy or colectomy.43 Dysplastic areas may appear flat or only slightly elevated above the level of the mucosa, or they may occur within or near a lesion or mass. The latter are referred to as a dysplasiaassociated lesion or mass (DALM) and have been highly as-
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Parsia A. Vagefi, Walter E. Longo sociated with the presence of invasive colorectal cancer.44-46 Indeed, detection of a DALM has often been considered justification for colectomy. As the risk for sporadic adenomas in patients with IBD is similar to that of the general population, sporadic adenomas must be distinguished from a DALM in order to prevent unnecessary colectomy. Two molecular markers have been proposed for distinguishing DALM from sporadic adenomas: β-catenin (a cell membrane protein) and p53 (a tumor suppressor gene). In a comparison of DALM specimens with sporadic adenomas it was demonstrated that positive staining for β-catenin was more common in sporadic adenomas than in DALM (40% vs. 8%), whereas positive staining for p53 was more common in DALM than in sporadic adenomas (29% vs. 5%).47
Colonoscopic Surveillance As with the finding of a DALM, there is a general consensus that the finding of high-grade dysplasia during colonoscopic surveillance warrants prompt colectomy, because patients with high-grade dysplasia have a 30%-40% risk of concurrent or imminent CRC.43,46 However, there is less agreement regarding the optimal strategy for the management of low-grade dysplasia detected upon colonoscopic surveillance, as its predictive value for progression to high-grade dysplasia or neoplasia has remained unclear.48 Thus, the outcome following the detection of a low-grade dysplastic lesion has been early colectomy or continued surveillance, depending on the practitioner. However, a recent retrospective study, albeit with a limited sample size, has demonstrated that a finding of flat low-grade dysplasia during surveillance in patients with UC is a strong predictor of progression to advanced neoplasia (high-grade dysplasia or CRC) and that early colectomy should be recommended for such patients.50 This study, which included 46 patients with UC and the detection of lowgrade dysplasia, demonstrated a rate of progression to highgrade dysplasia or CRC of 53% at 5 years in those patients who continued in the surveillance program. Of the 11 patients who underwent colectomy within 6 months of the diagnosis of low-grade dysplasia, 18% had CRC, all of which were stage I. In contrast, 20% of the 35 patients who elected not to undergo immediate colectomy, but continued surveillance, were diagnosed with CRC, which included stage II (40% of those diagnosed) and stage III (60% of those diagnosed) neoplasms. Importantly, the authors noted that the natural history of low-grade dysplastic lesions, in terms of the potential for regression or the step-wise progression to high-grade dysplasia and then CRC, remains controversial.48 Attempting to balance the risk of CRC development in a patient with IBD, versus the short- and long-term morbidity and mortality from surgery, will challenge the most experienced of practitioners. Although the data for risk reduction of CRC mortality by immediate colectomy for patients with low-grade dysplasia continue to deserve investigation, there is growing evidence that immediate colectomy may result in better survival than implementation of continued surveillance in patients with lowgrade dysplasia.
Observational evidence has suggested the potential benefit for colonoscopic surveillance in patients with chronic extensive colitis in order to identify patients with dysplasia and thus prevent malignant transformation; however, there remains an absence of published randomized controlled trials or epidemiologic studies that demonstrate a reduction in the mortality rate of CRC in patients with IBD following the implementation of a colonoscopic surveillance program.49 The goal of colonoscopic surveillance programs has been the early detection of dysplasia, as patients diagnosed with CRC after the onset of symptoms (ie, abdominal pain or bleeding) have been shown to have a worse prognosis than those detected during surveillance.50 Although surveillance colonoscopy has gained wide acceptance among practitioners, the optimal surveillance strategy for CRC in patients with IBD has yet to be established. Therefore, multiple recommendations have been issued by major societies, including the American Gastroenterological Association, the American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, and the British Society of Gastroenterology. It is the opinion of the authors, based upon best-practice patterns, that patients with ulcerative pancolitis or Crohn’s colitis who are surgical candidates should undergo surveillance colonoscopy after 8 years of disease, followed by annual colonoscopic examinations. Four biopsies should be obtained every 10 cm from the cecum to the rectum, and, in addition, any suspicious lesions or masses should be biopsied. Patients with left-sided UC should begin colonoscopic evaluations after 15 years of disease and then followed by annual colonoscopic examinations. Surveillance for patients with ulcerative proctitis is not recommended. Colectomy should be recommended for patients who are found to have high-grade dysplasia, lowgrade dysplasia, or a DALM, assuming the DALM has been distinguished from a sporadic adenoma. Based upon the inherent limitations of colonoscopic surveillance with random biopsies for the detection of dysplastic changes, practitioners have begun to investigate newer techniques that could assist in the detection of dysplasia or cancer. Although certain novel techniques are in their infancy, their potential for earlier and more accurate detection of dysplasia in surveillance programs for patients with IBD warrants their being mentioned. Sialosyl-Tn is a mucin-associated carbohydrate antigen whose expression in nondysplastic colonic mucosa may precede the development of neoplasia in patients with long-standing UC.51 Immunohistochemical staining directed for this cell surface marker may serve as a useful adjunct to colonoscopic surveillance with random biopsies. The detection of allelic deletions and point mutations of tumor suppressor genes (such as p53, Rb, mcc, and APC) may also provide for improved surveillance, as these genes may be involved in the tumorigenesis of CRC in patients with IBD.52 Advances in flow cytometric analysis for the detection of DNA aneuploidy in mucosal specimens of patients with UC may improve the utility of colorectal surveillance, as it has been shown that changes in nuclear DNA
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Inflammatory Bowel Disease and Colon Cancer content appear to precede dysplasia in the malignant transformation of colonic mucosa in UC.53
Chromoendoscopy Chromoendoscopy involves the topical application of stains or pigments to assist in tissue localization, characterization, or diagnosis during gastrointestinal endoscopy.54 The staining of the gastrointestinal mucosa further defines the mucosal surface and, when used in conjunction with magnifying colonoscopy, may assist in the detection of mucosal alterations and allow for more targeted biopsies of the colonic epithelium. A recent randomized, controlled trial demonstrated that colonic mucosal staining with methylene blue enhanced the ability to delineate the extent of inflammatory changes by an average of 14 cm. In addition, and more important, the chromoendoscopy identified significantly more neoplastic lesions, in comparison with routine surveillance colonoscopy with random biopsy in patients with UC.55 The chromoendoscopy was performed by spraying the colonic mucosa with methylene blue 0.1% in 30-cm segments. The mucosa was then examined with a magnifying endoscope, and, as the uptake of dye in the neoplastic epithelium is poor, biopsies were directed to the paler, less blue, or white areas.
Adjuvant Therapy Relapse for patients who have undergone potentially curative colonic resections is thought to surface from clinically silent micrometastases present at the time of operation. Thus, the goal of postoperative adjuvant therapy has been to decrease the recurrence rate following curative resection by eradicating micrometastases, thus enhancing rates of survival. Although most of the literature concerning adjuvant systemic chemotherapy for colonic cancer is based on data from the non-IBD population, the advantages of adjuvant therapy are likely applicable to both populations with colon cancer. Much like patients with sporadic colon cancer, survival in patients with IBD who develop colon cancer has been shown to be stage dependent.56 Currently, the available data support the routine use of adjuvant 5-fluorouracil (5-FU)–based systemic therapy in patients with stage III disease following resection. The use of adjuvant therapy in this setting has demonstrated reduction in the risk of recurrence and death from colon cancer.57 In contrast, the use of adjuvant chemotherapy in patients with stage II disease remains a controversial topic and is currently being considered for patients with high-risk stage II disease. This includes patients with obstruction, perforation, T4 lesions, or T3 lesions with a depth of invasion > 15 mm beyond the outer border of the muscularis propria.58 The improvement in reduction of stage III mortality with combination 5-FU/leucovorin (LV), as opposed to 5-FU/levamisole, has allowed 5-FU/LV to remain the standard of care in the adjuvant treatment of colon cancer. However, the arsenal of adjuvant chemotherapy for colon cancer is rapidly expanding, as recent data from the MOSAIC trial have demonstrated that the combination of oxaliplatin with 5-FU/LV
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(FOLFOX) is superior in 3-year disease-free survival compared with 5-FU/LV in the adjuvant treatment of colon cancer.59 Investigations into the use of irinotecan combined with FOLFIRI (infusional 5-FU/LV), as well as the use of monoclonal antibodies bevacizumab (antivascular endothelial growth factor) and cetuximab (antiepidermal growth factor receptor) in the treatment of colonic carcinoma, are also under way.60 These recent and dramatic advances in adjuvant chemotherapy for colon cancer hold promise to reduce mortality from colonic carcinoma following surgical curative resection in the IBD and non-IBD populations.
Conclusion Although only a small portion of the total number of cases of CRC, the development of a colonic neoplasm remains the most frequent malignant complication in patients with IBD and accounts for 15% of all deaths in patients with IBD. Since the first description of the association between UC and CRC in 192561 and subsequent descriptions of the similar risk of CRC in CD,17 practitioners have sought to further delineate the process by which the colonic epithelium in patients with IBD undergoes tumorigenesis. Although surgery remains a mainstay in the prevention and treatment of CRC in the patient with IBD, ongoing investigations into the treatment of IBD and the prevention and earlier detection of dysplastic changes within the colonic epithelium may produce significant reductions in the risk of development of CRC.
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