AGA

AGA Medical Position Statement on the Diagnosis and Management ofColorectal Neoplasia in Inﬂammatory Bowel Disease

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterologist (Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, James D. Lewis, MD, and Thomas A. Ullman, MD), an insurance provider representative (Tom James III, MD Physician Advisor, Strategic Advisory Group, Humana), a colon and rectal surgeon (Robin McLeod, MD, Mount Sinai Hospital-Canada), a pathologist (Lawrence J. Burgart, MD, Minnesota Gastroenterology), chair of the AGA Institute Clinical Practice and Quality Management Committee (John Allen, MD, Minnesota Gastroenterology), and chair of the Practice Management and EconomicsCommittee (Joel V. Brill, MD, Predictive Health, LLC).

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n this medical position statement, a series of questionswere identiﬁed that are relevant for clinicians who man-age patients with inﬂammatory bowel disease (IBD) at riskfor colorectal neoplasia (Table 1). For each question, a comprehensive literature search was conducted, pertinentevidence was reviewed, and the quality of relevant data wasevaluated. The details of the methodology used for theliteraturesearchassociatedwithansweringeachoftheques-tions appear in the following text. The conclusions werebased on the best available evidence or, in the absence of quality evidence, the expert opinion of the authors of thetechnical review

and the medical position statement. Someof the conclusions constitute recommendations for preven-tion. The strength of these recommendations was weighedusing the US Preventive Services Task Force (USPSTF)grades, which are detailed inTable 2.

Literature Search Methodology

A search of the MEDLINE database was performedto identify relevant English language articles published inpeer-reviewed journals. For this search, the terms dysplasia,colorectal cancer, surveillance, polyp, chemoprevention,chromoendoscopy, endoscopy, primary sclerosing cholangi-tis, risk factors, and children were searched in combinationwith the terms ulcerative colitis, Crohn’s disease, Crohn’scolitis, colitis, or inﬂammatory bowel disease. A manualsearch of the reference lists from the potentially relevantpapers was performed to identify additional studies thatmay have been missed using the computer-assisted strategy.In most instances, the pathology studies represented retro-spective case-control, or cohort studies, descriptive studies,reports of expert committees, or opinions of respected au-thorities in pathology practice.

Are Patients With IBD at IncreasedRisk for Colorectal Cancer?

I. Patients with ulcerative colitis and Crohn’s disease of thecolon have an increased risk of developing colorectal cancer.

Patients with IBD have an increased risk of devel-oping colorectal cancer (CRC). The exact magnitude of the risk is uncertain due to wide variations in risk re-ported in many studies. Variations occur because somestudies reported data only from tertiary referral centers,some were population based, and others represented only case reports or small series. Meta-analyses have beenperformed in both patients with ulcerative colitis (UC)and patients with Crohn’s disease (CD).From one large meta-analysis, the risk of cancer in pa-tients with UC is estimated at 2% after 10 years, 8% after 20years, and 18% after 30 years of disease. Data from a UK30-year surveillance program calculated the risk of cancerand dysplasia to be 7.7% at 20 years and 15.8% at 30 years.Subsequent population-based studies have suggested thatthe risk may not be this high and that the risk has actually decreased over time. This may be due to widespread use of aminosalicylates, which are believed to have a chemoprotec-tive effect, or to more liberal and early use of colectomy formedically refractory disease in some centers, and possibly surveillance colonoscopy.

Abbreviations used in this paper:

CI, conﬁdence interval; CRC, colo-rectal carcinoma; DALM, dysplasia-associated lesion or mass; HGD,high-grade dysplasia; LGD, low-grade dysplasia; PSC, primary scleros-ing cholangitis; USPSTF, US Preventive Services Task Force.

2010 by the AGA Institute0016-5085/10/$36.00doi:10.1053/j.gastro.2009.12.037

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GASTROENTEROLOGY 2010;138:738–745

In CD, there has also been wide variation in the reportedrisk of CRC due to inconsistencies in studies. For instance,some studies only included patients with small bowel dis-ease and colonic resections, and others did not account forduration of disease. Two meta-analyses that adjusted forthese factors have reported the standardized incidence ratiofor CRC as 2.5 (95% conﬁdence interval [CI], 1.7–3.5) andthe relative risk (RR) as 4.5 (95% CI, 1.3–14.9). Studies thatincluded patients with both UC and CD have shown therisk to be roughly equivalent in both diseases (RR of 2.75and 2.64, respectively). In addition, many of the character-istics of CRC in UC and CD have been shown to be similar.Thus, extensive Crohn’s colitis should raise the same con-cerns regarding CRC risk as UC.

Are There Well-Substantiated FactorsOther Than Dysplasia That Increase orDecrease the Risk of CRC in IBD?

I. Disease duration, more extensive disease, primary scleros-ing cholangitis, and a positive family history of sporadicCRC are all associated with an increased risk of CRC.II. Colonic strictures in patients with UC and/or a short-ened colon, and/or multiple postinﬂammatory pseu-dopolyps increase the risk of CRC.III. Inﬂammation is a risk factor for progression to colo-rectal neoplasia.

Increasing duration of disease is firmly establishedas one of the most important risk factors for the develop-ment of CRC in patients with IBD. The risk of CRC issignificant after 8 years of disease and increases in subse-quent years. A small proportion of cancers may arise before8 years, but because this is so infrequent, it does not justify commencing surveillance earlier than 8 years. Rather, it ismore appropriate to focus surveillance on patients whohave a higher risk as a result of other risk factors.Extent of disease is also a major risk factor for CRC inpatients with IBD. Most cancers arise in patients withpancolitis. There is an intermediate risk for patients withleft-sided disease (disease up to the splenic flexure),whereas patients with proctitis or ulcerative proctosig-moiditis have either little or no increased risk of CRC.Extent of disease is defined by the most extensive diseaseidentified at any time histologically. A colonoscopy isadvised after 8 years of disease to redefine the extent of disease and to decide on subsequent surveillance inter- vals. Two studies have examined backwash ileitis asan independent risk factor for development of CRC.These studies showed contrasting results. Thus, atpresent, there is insufficient evidence to consider back-wash ileitis as an independent risk factor for CRC inpatients with IBD.There is good evidence showing that primary scleros-ing cholangitis (PSC) is associated with an increased riskof CRC. From one meta-analysis, the risk of CRC wascalculated to be increased 4-fold compared to patientswith UC but without PSC. The increased risk was shownto persist after liver transplantation, at a rate of 1% perperson per year. Patients with PSC may have subclinicalUC for many years before their diagnosis of PSC. Thus,patients with UC (or Crohn’s colitis) and PSC are recom-mended to commence annual colonoscopy from the timeof diagnosis of PSC and are also recommended to con-tinue surveillance after (possible) liver transplantation. A positive family history of sporadic CRC in a first-degree relative of a patient with IBD doubles the risk of

Table 1.

Questions Relevant for Clinicians Who ManagePatients With IBD at Risk for Colorectal Neoplasia

1. Are patients with IBD at increased risk for colorectal cancer?2. Are there well-substantiated factors other than dysplasia thatincrease or decrease the risk of CRC in IBD?3. What is the natural history of dysplasia?4. Should colectomy be performed for raised dysplasia?5. Should colectomy be performed for ﬂat dysplasia?6. Is there sufﬁcient rationale for performing surveillancecolonoscopy in patients with IBD?7. How should surveillance colonoscopy be performed?8. What role do the newer imaging techniques play in identifyingand managing dysplasia?9. Should chemopreventive agents be used to lower the risk of developing dysplasia or CRC in IBD?10. Should molecular markers be applied to help stratify patientsinto low- and high-risk groups?

Table 2.

USPSTF Recommendations and Grades

Strength of recommendations:Grade A indicates that the certainty of evidence is high that themagnitude of net benefits is substantial. The USPSTF recommends providing the service for the specific population.Grade B indicates that the certainty of evidence is moderate thatthe magnitude of net benefits is either moderate orsubstantial, or that the certainty of evidence is high that themagnitude of net benefits is moderate. The USPSTF recommends providing the service for the specific population.Grade C indicates that the certainty of the evidence is either highor moderate that the magnitude of net benefits is small. TheUSPTF recommends against routinely providing the service forthe specific population. There may be considerations thatsupport providing the service in an individual patient.Grade D indicates that the certainty of the evidence is high ormoderate that the magnitude of net benefits is either zero ornegative. The USPSTF recommends against providing theservice for the specific population.Grade I indicates that the evidence is insufficient to determinethe relationship between benefits and harms (ie, net benefit).The USPSTF concludes that the current evidence is insufficientto assess the balance of benefits and harms of the service inthe specific population.US Preventive Services Task Force Procedure Manual. AHRQPublication No. 08-05118-EF, July 2008. Available at:http://www.ahrq.gov/clinic/uspstf08/methods/procmanual.htm.

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CRC. The risk increases 9-fold if the first-degree relativewas younger than 50 years of age at the time of diagnosisof CRC. A positive family history should be regarded asan important independent risk factor, but it is not yetclear whether this variable should influence surveillanceintervals. A greater degree of macroscopic and histologic inflam-mation is associated with an increased risk of cancer.CRC can arise in areas of endoscopically normal buthistologically active colitis. CRC can also occur in areaswhere active colitis has remitted, that is, areas wherethere is no active inflammation but where there may behistologic findings of inactive colitis, such as crypt dis-tortion. Lack of endoscopic inflammation at the time of detection of neoplasia does not mean that there was anabsence of inflammation in the area of neoplasia beforeits development. The risk of neoplasia is not increased inmucosa that has never been inflamed. Thus, histologicrather than macroscopic changes of disease are a betterdeterminant of the presence or absence of inflammationfor the purpose of assessing cancer risk. For the purposeof surveillance, extent of disease should be defined his-tologically. For example, a patient with evidence of en-doscopic disease up to 10 cm but with active or chronicinflammation (or documented evidence of previous in-flammation) up to 60 cm documented histologically,should be surveyed as if he or she has left-sided colitisand not proctitis.It has been reported that strictures, especially in UC,and the presence of a shortened colon (representing long-standing inflammation) are associated with an increasedrisk of CRC. Extra vigilance is required by the colonos-copist in patients with any of these features, and extra biopsies are highly recommended. Multiple postinflam-matory pseudopolyps have been shown to double the riskof CRC. Surveillance may have reduced benefit in thecontext of multiple pseudopolyps, and thus affected pa-tients should be made aware of this limitation. Somepatients may choose prophylactic colectomy over contin-ued surveillance in this circumstance.Early age at onset of IBD symptoms has not beenconsistently shown to represent an independent risk fac-tor of CRC. It has been reported that the cumulative riskof CRC in patients with extensive UC is 40% in whom thedisease began before 15 years of age and 25% in patientswho develop UC between 15 and 39 years of age. Otherdata that suggest an increased risk of CRC in patientswith IBD diagnosed after the age of 40 years may reflecta contribution from the age-related risk of developingsporadic CRC. Children diagnosed with IBD have at leastan equivalent rate of CRC development compared topatients diagnosed at an older age. Thus, surveillanceshould be conducted as frequently in children as inadults and should be based on duration of disease, notchronological age.

What Is the Natural History of Dysplasia?

I. In most cases, CRC in IBD develops from dysplasia.II. Although imperfect, dysplasia is currently considered thebest marker of CRC risk in IBD.

Dysplasia is currently considered the best markerof CRC risk in IBD, but there are limitations in predict-ing the natural history of dysplasia. Although dysplasia ispresent in 75% to 90% of patients with cancer, CRC candevelop in patients without a prior history of dysplasia. Also, not all patients with low-grade dysplasia (LGD) willprogress through a phase of detectable high-grade dys-plasia (HGD) before developing cancer. Importantly, theinterpretation of dysplasia in mucosal biopsy specimensis subject to a high level of interobserver variability. Thus,pathologists with particular expertise in gastrointestinaldisorders should review all cases diagnosed as indefinite,LGD, or HGD. Until more reliable markers of cancer riskare identified, clinical management depends on the en-doscopic and histologic identification of dysplasia inmucosal biopsy specimens of the colon. In patients foundto have dysplasia on one colonoscopy, the absence of dysplasia on follow-up colonoscopy does not providereassurance that the risk of CRC has declined. Patientswith biopsy specimens that show indefinite dysplasia have a risk of progression to HGD or CRC higher than inpatients without dysplasia. Unifocal low-grade dysplasia has been shown to carry a similar risk of CRC as multi-focal dysplasia in one study, but this remains to beconfirmed in other studies.

Should Colectomy Be Performed forRaised Dysplasia?

Grade A: High certainty that the magnitude of netbeneﬁts is substantial.

I. Patients with IBD and a non–adenoma-like dysplasia-associatedlesionormassshouldbetreatedwithcolectomy.II. Patients with IBD and an adenoma-like dysplasia-associ-ated lesion or mass, and no evidence of ﬂat dysplasiaelsewhere in the colon, can be managed safely by polypec-tomy and continued surveillance.

Raised, endoscopically visible, dysplastic lesions inIBD have been referred to by the acronym “DALM” (dys-plasia-associated lesion or mass). Recent studies suggestthat IBD-related DALMs may be broadly separated intothose that appear similar to sporadic adenomas in non-IBD patients, referred to as adenoma-like DALMs, andthose that do not resemble adenoma-like DALMs, whichare referred to as non–adenoma-like DALMs. Both types