It has been proposed that effective disease control through abrogation of inflammation in IBD may also reduce CRC risk in these individual patients. This article summarizes the potential for medical therapy to reduce the risk of CRC via primary and secondary prevention, and offers practical ways in which a goal of mucosal improvement or healing may be incorporated into clinical practice.
Key points
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Medical therapy, as in the case of 5-aminosalicylic acid, may have mechanistic plausibility for direct antineoplastic properties, but others, such as thiopurines, do not, suggesting that there is a primary chemopreventive benefit derived from the ability to achieve endoscopic and histologic healing.
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Mucosal healing induced by medical therapy may also provide a secondary preventive benefit by allowing improved endoscopic and histologic detection and differentiation between reactive epithelial changes and dysplasia.
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Of the many risk factors for the development of colitis-associated colorectal cancer (CRC), one of the most modifiable for a treating physician is the presence and severity of chronic inflammation.
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Although the mechanism of the declining risk of CRC in IBD is unclear, the likely determinants are a combination of primary prevention resulting from improved medical therapies able to induce mucosal healing, and secondary prevention derived from improved surveillance endoscopy technologies.
Introduction
Current goals of therapy for inflammatory bowel disease (IBD) are the induction and maintenance of inflammatory symptoms to provide an improved quality of life, to reduce the need for long-term corticosteroids, and to reduce other long-term outcomes such as disability, hospitalization, and colorectal cancer (CRC). Although the success of this latter goal has been difficult to measure, the overall risk of IBD-associated colorectal cancer (CRC) appears to have declined over the past 30 years. The observed decrease in CRC is thought to be due to a combination of factors, including improvements in the ability to identify and to quantify patients at risk and to detect precancerous lesions, and the direct and indirect reduction in cancer resulting from effective medical and surgical therapies of the underlying inflammation.
Some of the well-defined genetic molecular pathways leading to sporadic or hereditary CRC also appear to be present in colitis-associated CRC. However, IBD-associated adenocarcinoma does not seem to follow the discrete adenoma-to-CRC sequence of events. Rather, a progression, from inflamed mucosa to low-grade dysplasia (LGD) to high-grade dysplasia (HGD) to invasive adenocarcinoma, in IBD remains presumed and unproven. In fact, neoplasia in colitis takes different forms, a fact that has resulted in difficulty classifying, identifying, and developing appropriate prevention strategies for it. Cells from colonic mucosa in patients with chronic colitis have the molecular fingerprints of dysplasia and cancer, including genomic instability (aneuploidy), aberrant DNA methylation, and p53 mutations, even before there is any histologic evidence of dysplasia or cancer. It is thought that such a “field effect” of CRC risk is induced by chronic long-standing mucosal inflammation.
Most recently, the degree of inflammation has been shown to be a significant risk factor for neoplasia in IBD. In addition to the presence and degree of severity of active endoscopic/histologic colonic inflammation, additional established IBD-associated dysplasia and CRC risk factors include extent and duration of disease, family history of CRC, concomitant primary sclerosing cholangitis (PSC), young age at diagnosis, and presence of postinflammatory polyps and strictures. Of these risks, the only modifiable risk factor may be the degree of active inflammation. Therefore, it has been proposed that effective disease control through abrogation of inflammation may also reduce CRC risk in the individual patient.
Although the culmination of this evidence to date supports the clinician-adopted theory that treating to achieve mucosal healing will reduce the risk of CRC in patients with IBD, it remains uncertain how these recommendations can be practically applied by clinicians trying to develop effective dysplasia and CRC prevention strategies in IBD. This article summarizes the potential for medical therapy to reduce the risk of CRC via primary and secondary prevention, and offers practical ways in which a goal of mucosal improvement or healing may be incorporated into clinical practice ( Box 1 ).
Primary chemoprevention
Medical therapy reduces inflammation over time
Medical therapy has unique chemoprotection mechanisms
Secondary prevention
Treatment to achieve a healed bowel results in more accurate neoplasia detection by endoscopy
Reduction in histologic inflammation improves pathologist’s diagnosis of neoplasia
Introduction
Current goals of therapy for inflammatory bowel disease (IBD) are the induction and maintenance of inflammatory symptoms to provide an improved quality of life, to reduce the need for long-term corticosteroids, and to reduce other long-term outcomes such as disability, hospitalization, and colorectal cancer (CRC). Although the success of this latter goal has been difficult to measure, the overall risk of IBD-associated colorectal cancer (CRC) appears to have declined over the past 30 years. The observed decrease in CRC is thought to be due to a combination of factors, including improvements in the ability to identify and to quantify patients at risk and to detect precancerous lesions, and the direct and indirect reduction in cancer resulting from effective medical and surgical therapies of the underlying inflammation.
Some of the well-defined genetic molecular pathways leading to sporadic or hereditary CRC also appear to be present in colitis-associated CRC. However, IBD-associated adenocarcinoma does not seem to follow the discrete adenoma-to-CRC sequence of events. Rather, a progression, from inflamed mucosa to low-grade dysplasia (LGD) to high-grade dysplasia (HGD) to invasive adenocarcinoma, in IBD remains presumed and unproven. In fact, neoplasia in colitis takes different forms, a fact that has resulted in difficulty classifying, identifying, and developing appropriate prevention strategies for it. Cells from colonic mucosa in patients with chronic colitis have the molecular fingerprints of dysplasia and cancer, including genomic instability (aneuploidy), aberrant DNA methylation, and p53 mutations, even before there is any histologic evidence of dysplasia or cancer. It is thought that such a “field effect” of CRC risk is induced by chronic long-standing mucosal inflammation.
Most recently, the degree of inflammation has been shown to be a significant risk factor for neoplasia in IBD. In addition to the presence and degree of severity of active endoscopic/histologic colonic inflammation, additional established IBD-associated dysplasia and CRC risk factors include extent and duration of disease, family history of CRC, concomitant primary sclerosing cholangitis (PSC), young age at diagnosis, and presence of postinflammatory polyps and strictures. Of these risks, the only modifiable risk factor may be the degree of active inflammation. Therefore, it has been proposed that effective disease control through abrogation of inflammation may also reduce CRC risk in the individual patient.
Although the culmination of this evidence to date supports the clinician-adopted theory that treating to achieve mucosal healing will reduce the risk of CRC in patients with IBD, it remains uncertain how these recommendations can be practically applied by clinicians trying to develop effective dysplasia and CRC prevention strategies in IBD. This article summarizes the potential for medical therapy to reduce the risk of CRC via primary and secondary prevention, and offers practical ways in which a goal of mucosal improvement or healing may be incorporated into clinical practice ( Box 1 ).
Primary chemoprevention
Medical therapy reduces inflammation over time
Medical therapy has unique chemoprotection mechanisms
Secondary prevention
Treatment to achieve a healed bowel results in more accurate neoplasia detection by endoscopy
Reduction in histologic inflammation improves pathologist’s diagnosis of neoplasia
Definition of remission in IBD: an evolving target
The end point of escalation of therapy in IBD has traditionally been based on adequate symptom control. Despite patient satisfaction in the achievement of clinical remission, in many patients this goal is believed to be insufficient in achieving additional goals of stable remission over time and changing the natural history of the disease. In fact, multiple lines of investigation have demonstrated that a significant proportion of IBD patients in clinical (symptomatic) remission continue to have active mucosal inflammation, both endoscopically and histologically. In addition, a prospective study in patients with active colonic or ileocolonic Crohn’s disease treated with steroids found no correlation between the clinical activity index and any of the endoscopic data, and although 92% of patients achieved clinical remission, less than one-third of patients also achieved concomitant endoscopic remission.
Clinically the achievement of a healed mucosa has been associated with a modified course of IBD, including a reduction in rates of clinical relapse, fewer inpatient hospitalizations, and decreased lifetime risk of surgery. Evidence that a healed bowel mitigates the development of IBD-associated dysplasia and CRC has been insufficient. With the increased interest in endoscopic mucosal healing in clinical trials, it is hoped that additional evidence will demonstrate a direct link between this end point and subsequent reduction in CRC risk. Clinical trials to date have varied definitions ranging from endoscopic resolution of all mucosal ulcerations to endoscopic scoring indices, with very few studies evaluating histologic healing. Therefore, a remaining challenge is this discrepancy between the clinical trials definition of mucosal healing through endoscopic measures and the available evidence related to risk for neoplasia in colitis, which is histologically measured. More recently, the US Food and Drug Administration has expressed interest in histologic assessment of bowel healing, which undoubtedly will lead to additional study and resource allocation.
Nonetheless, as the bar is raised to achieve deeper levels of mucosal healing, one of the significant challenges is the poor correlation between macroscopic mucosal healing as gauged by endoscopic assessment and endoscopist interpretation, and histologically measured disease control as measured by biopsy sampling and pathologist interpretation. In a study of 152 IBD patients in clinical remission undergoing routine surveillance colonoscopy, Baars and colleagues found that only 67% of patients in clinical remission had histologically active inflammation, and of these patients 50% were endoscopically normal. Similarly, in a study of 82 asymptomatic patients with ulcerative colitis (UC), Rubin and colleagues identified that more than 30% of patients had endoscopic inflammation and 89% had histologic evidence of active inflammation. If it is considered that a strict definition of mucosal healing should include resolution of histologic inflammation in addition to an endoscopic assessment of healing, these studies demonstrate the real-world challenge to this approach and emphasize the importance of further study.
A well-described challenge to the use of mucosal healing as a primary end point of the treatment of IBD is the trade-off between risks and benefits (and costs) in patients who feel well, but require escalation of therapy to achieve deeper levels of disease control. It is unclear whether such additional disease control is possible, and whether patients will be willing to escalate their therapy to achieve such control when they are already in clinical remission. Will such dose or class escalation result in more adverse events than benefits? Will it result, as the available evidence thus far suggests, in most patients “burning” through all of the available therapies and never achieving this level of inflammation control? How will the loss of this level of control and so-called disease drift be monitored? How often, and how invasive will repeated assessments be needed? Obviously there remain many unanswered questions before a disease-wide modification in treatment goals can be applied. Nonetheless, there are ongoing efforts to apply a treat-to-target approach used in other chronic diseases to IBD. Such paradigm shifts in management will answer these questions and guide future therapies.
Treatment to mucosal healing may improve detection of neoplasia in IBD
Being able to accurately detect precancerous lesions in patients with colonic IBD is requisite for screening colonoscopy and subsequent interval surveillance examinations. IBD-associated colorectal neoplasia may be a challenge to detect endoscopically because it may be multifocal, broadly infiltrating, and arising from flat mucosa, and therefore endoscopically indistinct from the surrounding tissue. Therefore, to adequately sample representative mucosa and identify dysplasia histologically, historical (and current) guidelines endorsed by multiple societies suggest 4-quadrant random biopsy specimens obtained every 10 cm throughout the colon, aiming to obtain at minimum 32 biopsy samples. However, this approach is limited in that it samples less than 1% of colonic surface area and at the same time is subject to poor patient compliance with surveillance, lack of gastroenterologist knowledge, and compliant practice patterns, in addition to poor pathologist interobserver agreement for dysplasia diagnoses.
Furthermore, retrospective studies evaluating the visibility of dysplasia and CRC in patients with IBD have found that most dysplastic lesions are endoscopically visible. In a 14-year, retrospective review of 2204 surveillance colonoscopies, Rutter and colleagues found the neoplastic per-lesion and per-patient sensitivity to be 77.3% and 89.3%, respectively. A total of 22.7% of lesions were macroscopically invisible on colonoscopy. A 10-year, single-institution, retrospective study by Rubin and colleagues in the United States similarly found dysplasia or cancer had per-lesion and per-patient endoscopic visibility of 61.3% and 76.1%, respectively. In this series, 38 of 65 dysplastic lesions (58.5%) and 8 of 10 cancers (80.0%) were visible to the endoscopist as 23 polyps and masses, 1 stricture, and 22 areas of irregular mucosa. In this series 38.7% of lesions were endoscopically invisible, detected only by random biopsy. These retrospective studies did not account for the advent of newer advances in colonoscopic technology, including high-definition or image-enhancement endoscopy techniques such as chromoendoscopy, all of which are believed to further improve visualization and guide future preventive approaches.
In the setting of macroscopically active inflammation, the pathologic diagnosis of dysplasia is often more challenging, primarily because of the difficulty in differentiating inflammation-associated regenerative changes and true dysplasia. In the setting of healing UC, epithelial regeneration occurs with changes that may mimic dysplasia, especially in the eyes of the less experienced pathologist. The epithelial cells become cuboidal with eccentric, large nuclei, mucin depletion, and prominent nucleoli. As a result, pathologists may need to interpret such biopsy specimens as “indefinite for dysplasia” or undiagnosable for dysplasia. Therefore, in addition to the pursuit of mucosal healing as a method of primary prevention of dysplasia and CRC, its achievement may also provide benefit in secondary prevention of CRC, defined as the accurate detection of existing precancerous lesions by gastroenterologists and pathologists. Completing a surveillance colonoscopy in the setting of mucosal healing should improve visualization of neoplastic lesions for the endoscopist, and improve the ability of pathologists to distinguish regenerative change from true dysplasia.
Medical therapy as primary chemoprevention in IBD-associated neoplasia
The pathophysiology of colitis-associated dysplasia and cancer have implicated the molecular products of chronic inflammation from both innate and adaptive immune cells in the development of a risk-increasing “field effect” of genetic changes in IBD-associated neoplasia. This relationship is supported by the severity of histologic inflammation as an independent risk factor for neoplastic progression. In addition to directly reducing inflammation, medical therapy may play a primary chemopreventive role, altering the molecular pathways to dysplasia development ( Box 2 ).
5-Aminosalicylic acid
Thiopurine
Anti–tumor necrosis factor antibodies
Related posts:
Learning to Detect Flat Neoplastic Lesions in Inflammatory Bowel Disease
Quality Bowel Preparation for Surveillance Colonoscopy in Patients with Inflammatory Bowel Disease Is a Must
Image-Enhanced Endoscopy Is Critical in the Surveillance of Patients with Colonic IBD
The Unique Pathology of Nonpolypoid Colorectal Neoplasia in IBD
Toward a Consensus on Endoscopic Surveillance of Patients with Colonic Inflammatory Bowel Disease
Surgical Management of Nonpolypoid Colorectal Lesions and Strictures in Colonic Inflammatory Bowel Disease
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