Colorectal cancer surveillance in inflammatory bowel disease:Practice guidelines and recent developments

Patients with long-standing inflammatory bowel disease(IBD)involving at least 1/3 of the colon are at increased risk for colorectal cancer(CRC).Advancements in CRC screening and surveillance and improved treatment of IBD has reduced CRC incidence in patients with ulcerative colitis and Crohn’s colitis.Most cases of CRC are thought to arise from dysplasia,and recent evidence suggests that the majority of dysplastic lesions in patients with IBD are visible,in part thanks to advancements in high definition colonoscopy and chromoendoscopy.Recent practice guidelines have supported the use of chromoendoscopy with targeted biopsies of visible lesions rather than traditional random biopsies.Endoscopists are encouraged to endoscopically resect visible dysplasia and only recommend surgery when a complete resection is not possible.New technologies such as virtual chromoendoscopy are emerging as potential tools in CRC screening.Patients with IBD at increased risk for developing CRC should undergo surveillance colonoscopy using new approaches and techniques.     

Cancer in inflammatory bowel disease

Patients with long-standing inflammatory bowel disease （IBD） have an increased risk of developing colorectal cancer （CRC）. Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeox, ycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn＇s disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal- anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.     

Colorectal cancer and dysplasia in inflammatory bowel disease

Both ulcerative colitis and Crohn＇s disease carry an increased risk of developing colorectal cancer. Established risk factors for cancer among patients with inflammatory bowel disease （IBD） include the younger age at diagnosis, greater extent and duration of disease, increased severity of inflammation, family history of colorectal cancer and coexisting primary sclerosing cholangitis. Recent evidence suggests that current medical therapies and surgical techniques for inflammatory bowel disease may be reducing the incidence of this complication. Nonetheless heightened vigilance and a careful, comprehensive approach to prevent or minimize the complications of invasive cancer are warranted in this unique cohort of patients. Current guidelines for the prevention and early detection of cancer in this high risk population are grounded in the concept of an inflammation-dysplasia- carcinoma sequence. A thorough understanding of the definition and natural history of dysplasia in IBD, as well as the challenges associated with detection and interpretation of dysplasia are fundamental to developing an effective strategy for surveillance and prevention, and understanding the limitations of the current approach to prevention. This article reviews the current consensus guidelines for screening and surveillance of cancer in IBD, as well as presenting the evidence and rationale for chemoprevention of cancer and a discussion of emerging technologies for the detection of dysplasia.     

Microscopic features of colorectal neoplasia in inflammatory bowel diseases

The risk of developing dysplasia leading to colorectal cancer(CRC)is increased in both ulcerative colitis and Crohn’s disease.The prognosis of CRC may be poorer in patients with inflammatory bowel disease(IBD)than in those without IBD.Most CRCs,in general,develop from a dysplastic precursor lesion.The interpretation by the pathologist of the biopsy will guide decision making in clinical practice:colonoscopic surveillance or surgical management.This review summarizes features of dysplasia(or intraepithelial neoplasia)with macroscopic and microscopic characteristics.From an endoscopic(gross)point of view,dysplasia may be classified as flat or elevated(raised);from a histological point of view,dysplasia is separated into 3 distinct categories:negative for dysplasia,indefinite for dysplasia,and positive for dysplasia with low-or high-grade dysplasia.The morphologic criteria for dysplasia are based on a combination of cytologic(nuclear and cytoplasmic)and architectural aberrations of the crypt epithelium.Immunohistochemical and molecular markers for dysplasia are reviewed and may help with dysplasia diagnosis,although diagnosis is essentially based on morphological criteria.The clinical,epidemiologic,and pathologic characteristics of IBD-related cancers are,in many aspects,different from those that occur sporadically in the general population.Herein,we summarize macroscopic and microscopic features of IBD-related colorectal carcinoma.     

Clinical management of inflammatory bowel disease in the organ recipient

There was estimated a higher incidence of de novo inflammatory bowel disease(IBD)after solid organ transplantation than in the general population.The onset of IBD in the organ transplant recipient population is an important clinical situation which is associated to higher morbidity and difficulty in the medical therapeutic management because of possible interaction between anti-reject therapy and IBD therapy.IBD course after liver transplantation(LT)is variable,but about one third of patients may worsen,needing an increase in medical therapy or a colectomy.Active IBD at the time of LT,discontinuation of 5-aminosalicylic acid or azathioprine at the time of LT and use of tacrolimusbased immunosuppression may be associated with an unfavorable outcome of IBD after LT.Anti-tumor necrosis factor alpha(TNFα)therapy for refractory IBD may be an effective and safe therapeutic option after LT.The little experience of the use of biological therapy in transplanted patients,with concomitant anti-rejection therapy,suggests there be a higher more careful surveillance regarding the risk of infectious diseases,autoimmune diseases,and neoplasms.An increased risk of colorectal cancer(CRC)is present also after LT in IBD patients with primary sclerosing cholangitis(PSC).Anannual program of endoscopic surveillance with serial biopsies for CRC is recommended.A prophylactic colectomy in selected IBD/PSC patients with CRC risk factors could be a good management strategy in the CRC prevention,but it is used infrequently in the majority of LT centers.About 30%of patients develop multiple IBD recurrence and 20%of patients require a colectomy after renal transplantation.Like in the liver transplantation,anti-TNFαtherapy could be an effective treatment in IBD patients with conventional refractory therapy after renal or heart transplantation.A large number of patients are needed to confirm the preliminary observations.Regarding the higher clinical complexity of this subgroup of IBD patients,a close multidisciplinary approach between an IBD dedicated gastroenterologist and surgeon and an organ transplantation specialist is necessary in order to have the best clinical management of IBD after transplantation.     

Has the risk of colorectal cancer in inflammatory bowel disease decreased?

The association between inflammatory bowel disease(IBD)and colorectal cancer(CRC)has been acknowledged for almost a century and is assumedly promoted by a chronic inflammation-driven carcinogenic process in the intestine in combination with a genetic predisposition.The magnitude of the risk of CRC in IBD remains a continuing subject of debate.The early,high risk estimates for CRC in IBD were most likely overestimated due to selected patient populations originating from tertiary referral centers with a disproportional high percentage of patients with severe disease.Later population-based studies calculating risk estimates from a broad spectrum of IBD patients have found the risk to be significantly lower.At present,there is evidence that IBD patients with longstanding and extensive disease with uncontrolled inflammation are those at increased risk.Additional,other recognized risk factors include early age at onset,family history of CRC,and concomitant primary sclerosing cholangitis.A significant amount of effort is put into identifying potential preventive factors of CRC in IBD,including surveillance programs and chemopreventive agents but the individual effect of these remains uncertain.Interestingly,recent studies have reported a decline in risk of CRC over time.Surveillance programs and the new treatment strategies,particular biological treatment might be part of the reason for the observed decline in risk of CRC in IBD over time but future studies will have investigate this assumption.     

Surveillance of colonic polyps: Are we getting it right?

Colorectal cancer(CRC) is the third most commonly diagnosed cancer worldwide. The identification of colonic polyps can reduce CRC mortality through earlier diagnosis of cancers and the removal of polyps: the precursor lesion of CRC. Following the finding and removal of colonic polyps at an initial colonoscopy, some patients are at an increased risk of developing CRC in the future. This is the rationale for postpolypectomy surveillance colonoscopy. However, not all individuals found to have colonic adenomas have a risk of CRC higher than that of the general population. This review examines the literature on post-polypectomy surveillance including current international clinical guidelines. The potential benefits of surveillance procedures must be weighed against the burden of colonoscopy: resource use, the potential for patient discomfort, and the risk of complications. Therefore surveillance colonoscopy is best utilised in a selected group of individuals at a high risk of developing cancer. Further study is needed into the specific factors conferring higher risk as well as the efficacy of surveillance in mitigating this risk. Such evidence will better inform clinicians and patients of the relative benefits of colonoscopic surveillance for the individual. In addition, the decision to continue with surveillance must be informed by the changing profile of risks and benefits of further procedures with the patient’s advancing age.     

Colorectal cancer in inflammatory bowel disease:The risk,pathogenesis,prevention and diagnosis

Patients with inflammatory bowel disease(IBD)are at increased risk for developing colorectal cancer(CRC),although the overall incidence of IBD-associated CRC has been diminishing in recent decades in western countries.As demonstrated in previous studies,the risk of CRC in IBD increases with longer duration,extent of colitis,a familial history of CRC,coexistent primary sclerosing cholangitis,and the degree of inflammation.The pathogenesis of CRC in IBD is poorly understood.Similar to sporadic CRC,IBD-associated CRC is a consequence of sequential episodes of genomic alteration.Multiple inter-related pathways,including immune response by mucosal inflammatory mediators,oxidative stress,and intestinal microbiota,are also involved the pathogenesis of IBD-associated CRC.Continuing colonic inflammation appears to be a factor in the development of CRC;therefore,anti-inflammatory agents such as5-aminosalicylate compounds and immune modulators have been considered as potential chemopreventive agents.Colonoscopic surveillance is widely accepted as being effective in reducing the risk of IBD-associated CRC,although no clear evidence has confirmed that surveillance colonoscopy prolongs survival in patients with extensive colitis.The traditional recommendation has been quadrantic random biopsies throughout the entire colon;however,several guidelines now have endorsed chromoendoscopy with a target biopsy because of increasing diagnostic yields and reduced workloads for endoscopists and pathologists.New technologies such as narrow band imaging,confocal endomicroscopy,and autofluorescence imaging have not yet been confirmed as surveillance strategies in IBD.     

Endoscopy in inflammatory bowel disease when and why

Endoscopy plays an important role in the diagnosis and management of inflammatory bowel disease(IBD).It is useful to exclude other aetiologies,differentiate between ulcerative colitis(UC) and Crohn’s disease(CD),and define the extent and activity of inflammation.Ileocolonoscopy is used for monitoring of the disease,which in turn helps to optimize the management.It plays a key role in the surveillance of UC for dysplasia or neoplasia and assessment of post operative CD.Capsule endoscopy and double balloon enteroscopy are increasingly used in patients with CD.Therapeutic applications relate to stricture dilatation and dysplasia resection.The endoscopist’s role is vital in the overall management of IBD.     

5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) is classically subdivided into ulcerative colitis (UC) and Crohn's disease (CD). Patients with IBD have increased risk for colorectal cancer. Because the pathogenesis of colorectal carcinoma has not been entirely defined yet and there is no ideal treatment for colon cancer, cancer prevention has become increasingly important in patients with IBD. The two adopted methods to prevent the development of colon cancer in clinical practice include the prophylactic colectomy and colonoscopic surveillance. But patients and physicians seldom accept colectomy as a routine preventive method and most patients do not undergo appropriate colonoscopic surveillance. Chemoprevention refers to the use of natural or synthetic chemical agents to reverse, suppress, or to delay the process of carcinogenesis. Chemoprevention is a particularly useful method in the management of patients at high risk for the development of specific cancers based on inborn genetic susceptibility, the presence of cancer-associated disease, or other known risk factors. Prevention of colorectal cancer by administration of chemopreventive agents is one of the most promising options for IBD patients who are at increased risks of the disease. The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against intestinal tumors has been well established. But with reports that NSAIDs aggravated the symptoms of colitis, their sustained use for the purpose of cancer Chemoprevention has been relatively contraindicated in IBD patients. Another hopeful candidate Chemoprevention drug for IBD patients is 5-aminosalicylic acid (5-ASA), which is well tolerated by most patients and has limited systemic adverse effects, and no gastrointestinal toxicity. 5-ASA lacks the well-known side effects of longterm NSAIDs use. Retrospective correlative studies have suggested that the long-term use of 5-ASA in IBD patients may significantly reduce the risk of development of colorectal cancer. According to the literature, this agent might well satisfy clinical expectations with respect to a safe and effective chemopreventive agent.     

Screening and surveillance methods for dysplasia in inflammatory bowel disease patients: Where do we stand?

Patients with long-standing ulcerative colitis(UC) and extensive Crohn's colitis(CC) are at increased risk for dysplasia and colorectal cancer(CRC). Several studies have shown that UC extending proximal to the rectum, CC involving at least 1/3 of the colon, co-existence of primary sclerosing cholangitis, undetermined or unclassified colitis, family history of CRC and young age at diagnosis appear to be independent risk factors for inflammatory bowel disease(IBD)-related CRC. Therefore, screening and surveillance for CRC in IBD patients is highly recommended by international and national guidelines, whilst colonoscopy remains the unequivocal tool in order to detect potentially resectable dysplastic lesions or CRC at an early stage. Although the importance of screening and surveillance is widely proven, there is a controversy regarding the time of the first colonoscopy and the criteria of who should undergo surveillance. In addition, there are different recommendations among scientific societies concerning which endoscopic method is more efficient to detect dysplasia early, as well as the terminology for reporting visible lesions and the management of those lesions. This article concisely presents the main endoscopic methods and techniques performed for detecting dysplasia and CRC surveillance in patients with IBD focusing on their evidence-based accuracy and efficiency, as well as their cost-effectiveness. Finally, newer methods are mentioned, highlighting their applicability in daily endoscopic practice.     

Colorectal cancer in inflammatory bowel disease: What is the real magnitude of the risk?

The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) has been recognised since 1925 and still accounts for 10%-15% of deaths in IBD. IBD-associated CRC (IBD-CRC) affects patients at a younger age than sporadic CRC. The prognosis for sporadic CRC and IBD-CRC is similar, with a 5-year survival of approximately 50%. Identifying at risk patients and implementing appropriate surveillance for these patients is central to managing the CRC risk in IBD. The increased risk of colorectal cancer in association with IBD is thought to be due to genetic and acquired factors. The link between inflammation and cancer is well recognised but the molecular biology, immune pathobiology and genetics of IBD-CRC are areas of much ongoing research. This review examines the literature relating to IBD-CRC, focusing on the incidence of IBD-CRC and examining potential risk factors including age at diagnosis, gender, duration and extent of colitis, severity of inflammation, family history of sporadic CRC and co-existent primary sclerosing cholangitis (PSC). Confirmed risk factors for IBD-CRC are duration, severity and extent of colitis, the presence of co-existent PSC and a family history of CRC. There is insufficient evidence currently to support an increased frequency of surveillance for patients diagnosed with IBD at a younger age. Evidence-based guidelines advise surveillance colonoscopy for patients with colitis 8 to 10 years after diagnosis, with the interval for further surveillance guided by risk factors (extent of disease, family history of CRC, post-inflammatory polyps, concomitant PSC, personal history of colonic dysplasia, colonic strictures). There is a move away from using random colonic biopsies towards targeted biopsies aimed at abnormal areas identified by newer colonoscopic techniques (narrow band imaging, chromoendoscopy, confocal microendoscopy).     

Surveillance and management of colorectal dysplasia and cancer in inflammatory bowel disease: Current practice and future perspectives

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). Current guidelines recommend frequent surveillance colonoscopies for patients with at least left-sided ulcerative colitis, or Crohn's disease involving more than 30% of the colon. Surveillance allows for early detection and treatment of colorectal dysplasia and cancer. The first colonoscopy should be performed 8 to 10 years after onset of disease symptoms. European and British guidelines employ a risk-stratification algorithm that assigns patients to surveillance intervals of one, three or five years, whereas American guidelines recommend to perform surveillance every 1 to 3 years based on the (combined) presence of risk factors. Patients with concomitant primary sclerosing cholangitis are at an additionally increased risk, and should undergo annual surveillance starting immediately after the diagnosis. The current practice of surveillance is based on limited evidence, is resource intensive and cannot preclude the occurrence of interval carcinomas. Fortunately, advances in endoscopic techniques for mucosal visualisation, along with better control of inflammation, have resulted in a declining incidence of CRC in patients with IBD. Furthermore, advanced endoscopic resection techniques can be expected to result in a shift from surgical to endoscopic management of dysplastic lesions. In this review, we provide an up-to-date overview of colitis-associated CRC pathophysiology, epidemiology, surveillance practices, and management of dysplasia.     

Colorectal cancer in inflammatory bowel disease: Molecular and clinical considerations

Opinion statement Adenocarcinoma of the colon is an accepted and feared complication of chronic ulcerative colitis (UC) and colonic Crohn’s disease (CD). When cancer is identified, surgery is necessary, and unlike with sporadic colorectal cancer (CRC), in which partial colectomy is effective, proctocolectomy is required. As CRC is a rare complication of these diseases, studies of the pathogenesis are limited primarily to observational studies; thus, the mechanism and molecular events that lead to neoplastic change are not fully understood or well known. Precancerous dysplasia has been associated with concurrent or future CRC in UC and, although less studied, in CD, and is therefore considered a marker of cancer risk in inflammatory bowel disease (IBD). Risk factors for dysplasia and CRC in IBD include longer duration of disease, greater extent of disease, younger age at diagnosis, diagnosis with primary sclerosing cholangitis (PSC), family history of CRC, and possibly backwash ileitis and degree of inflammation of the bowel over time. Prevention of cancer in IBD has been focused on secondary measures of identifying dysplasia in flat mucosa or protruding lesions during surveillance colonoscopy with random biopsies and, when confirmed, performing proctocolectomy. Studies of primary prevention of dysplasia and CRC using chemopreventive agents have suggested a possible benefit with a number of agents. These include ursodeoxycholic acid (in patients with PSC and UC), aminosalicylates, and possibly statins.     

Surveillance of patients with inflammatory bowel disease

Patients with inflammatory bowel disease involving the colon are at increased risk for developing colorectal cancer. Colonoscopy surveillance is important to identify and treat IBD associated dysplasia. The SCENIC consensus provides evidence-based recommendations for optimal surveillance and management of dysplasia in IBD. Chromoendoscopy, with the surface application of dyes to enhance mucosal visualization, is the superior endoscopic surveillance strategy to detect dysplasia. Most dysplasia is visible, and can be endoscopically resected. Future studies should determine the effect of new surveillance strategies on the incidence of CRC and mortality in patients with IBD.     

Carcinogenesis in inflammatory bowel disease

Patients with longstanding ulcerative colitis (UC) and Crohn's disease (CD) have an increased risk of colorectal cancer (CRC). CRC accounts for approximately 15% of all deaths in patients with inflammatory bowel disease (IBD). The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat dysplastic tissue or dysplasia-associated lesions or masses. The risk of CRC for patients with IBD increases by 0.5-1% yearly, 8-10 years after diagnosis. Patients with a young age at disease onset, more extensive colitis, greater inflammatory burden, concomitant primary sclerosing cholangitis, and a family history of CRC are at greatest risk. Most cancers arise in pancolitis and there is little or no increased risk associated with proctitis while left-sided colitis carries an intermediate cancer risk. The CRC risk in patients with colonic CD is similar to that of UC. Colonic dysplasia is a precursor to CRC in IBD. There is no clear evidence that surveillance colonoscopy prolongs survival in patients with extensive colitis. Newer endoscopic and molecular techniques are being assessed for their effectiveness in augmenting conventional surveillance.     

Inflammatory bowel disease as a risk factor for colorectal cancer

Patients with long-term inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's colonic disease (CD) have an increased risk of colorectal carcinoma (CRC). Eaden's meta-analysis has shown that the risk for CRC in UC patients is 2% at 10 years, 8% at 20 years and 18% at 30 years of disease duration. It is now accepted that the risk of colorectal cancer is equivalent in both (UC and CD) conditions. Duration of disease is recognized to be the most important risk factor for CRC development. Extent of disease in another major risk factor. Most cancers arise in patients with extensive disease, which is generally defined as extension of inflammation beyond the hepatic flexure. It was demonstrated that proctitis and proctosigmoiditis posed no increased risk for patients with UC. Recent data from case control studies suggests that greater degrees of colonoscopic or histologically active inflammation are associated with an increased risk of CRC. Recently, it has been proven that shortened tubular colon, colonic stricture and postinflammatory polyps should be considered strong risk factors for CRC development. Primary sclerosing cholangitis (PSC) in patients with UC is associated with substantial risk of CRC. Screening colonoscopy should be performed in patients with UC after 8-10 years of disease. The interval between surveillance examinations is dependent on each individual's personal risk factors. In patients with a previous history of PSC, ongoing active inflammation, previous history of dysplasia or strictures, and strong family history of bowel cancer, annual surveillance is recommended. Colectomy is strictly recommended for patients who were diagnosed with flat high-grade dysplasia (HGD) or CRC and where the diagnosis was confirmed by expert gastrointestinal pathologists. In patients with a biopsy specimen considered indefinite for dysplasia, guidelines suggest colonoscopy between 3 and 12 months. Multifocal low-grade dysplasia (LGD) is a stronger indication for colectomy. The optimal colonoscopic surveillance interval for patients who were diagnosed with a flat LGD is still unknown, but 3-6 months is often recommended. Chemopreventive agents should be used to minimize the risk of developing dysplasia or CRC in IBD patients. It has been shown that mesalazine has a preventive effect for CRC and dysplasia.     

Dysplasia and colorectal cancer surveillance in inflammatory bowel disease

Introduction: Inflammatory bowel disease (IBD) patients are at an increased risk of developing colorectal cancer (CRC), a devastating complication of which intestinal dysplasia is the precursor. Considerable progress has been made to determine CRC risk in IBD, identification & management of dysplasia and preventative methods. Traditionally, surveillance colonoscopies with random colonic biopsies was used. However recent data suggests that chromoendoscopy is a better method of surveillance. Using 5-aminosalicylic acid agents primarily for chemoprevention is an ongoing debate however, when prescribed along with other strategies to control inflammation, their use is considered of benefit. This review presents current understanding of risk factors of neoplasia focusing on dysplasia and preventive strategies.

Areas covered: PubMed search was done using key words to assess current evidence. Along with genetics, risk factors, strategies that modify the risk of dysplasia, and CRC in IBD are discussed in detail.

Expert commentary: The role of our strategies in modifying CRC risk needs further assessment. Future research should aim to fill knowledge gaps such as high quality evidence for Chromoendoscopy and development of molecular markers for dysplasia detection. Our ultimate goal would be to eliminate CRC and is possible by better understanding of key pathogenic mechanisms in IBD.