Download - AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

8/14/2019 AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

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AGA

AGA Medical Position Statement on the Diagnosis and Management of

Colorectal Neoplasia in Inammatory Bowel Disease

The AGA Institute Medical Position Panel consisted of the authors of the technical review, a community-based gastroenterolo(Robert P. McCabe, MD, Minnesota Gastroenterology), academic-based gastroenterologists (Themistocles Dassopoulos, MD, Jam 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 EconomiCommittee (Joel V. Brill, MD, Predictive Health, LLC).

Podcast interview: www.gastro.org/gastropodcast .

In this medical position statement, a series of questionswere identied that are relevant for clinicians who man-age patients with inammatory 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 the

literature search associated with answering each of theques-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 1 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 in Table 2.

Literature Search Methodology A search of the MEDLINE database was performed

to 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, Crohns disease, Crohnscolitis, colitis, or inammatory 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 Crohns 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 Crohns 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, condence 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 Institute

0016-5085/10/$36.00doi:10.1053/j.gastro.2009.12.037

AGA

GASTROENTEROLOGY 2010;138:738745
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CRC. The risk increases 9-fold if the rst-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 inuence surveillance

intervals. A greater degree of macroscopic and histologic inam-

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 inammation but where there may behistologic ndings of inactive colitis, such as crypt dis-tortion. Lack of endoscopic inammation at the time of detection of neoplasia does not mean that there was anabsence of inammation in the area of neoplasia beforeits development. The risk of neoplasia is not increased in

mucosa that has never been inamed. Thus, histologicrather than macroscopic changes of disease are a betterdeterminant of the presence or absence of inammationfor the purpose of assessing cancer risk. For the purposeof surveillance, extent of disease should be dened his-tologically. For example, a patient with evidence of en-doscopic disease up to 10 cm but with active or chronicinammation (or documented evidence of previous in-ammation) 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 inammation) 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 postinam-matory pseudopolyps have been shown to double the riskof CRC. Surveillance may have reduced benet 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 been

consistently 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 reecta 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 in

adults 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 the

best 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 indenite,LGD, or HGD. Until more reliable markers of cancer riskare identied, clinical management depends on the en-doscopic and histologic identication 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 indenite 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 beconrmed in other studies.

Should Colectomy Be Performed forRaised Dysplasia?

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

I. Patients with IBD and a nonadenoma-like dysplasia-associated lesion or mass should be treated with colectomy.

II. Patients with IBD and an adenoma-like dysplasia-associ-ated lesion or mass, and no evidence of at 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, and

those that do not resemble adenoma-like DALMs, whichare referred to as nonadenoma-like DALMs. Both types

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of DALMs are typically composed of dysplastic columnarcells that resemble those of sporadic neoplasia. Adeno-ma-like DALMs represent well-circumscribed, smooth orpapillary nonnecrotic, sessile or pedunculated polyps thatare usually readily accessible to removal by routine endo-

scopic methods. Other synonyms used to describe this le-sion include adenoma-like polyp, adenoma-like dysplasticpolyp, polypoid dysplasia, and adenoma-like mass. Nonadenoma-like DALMs include velvety patches, plaques, ir-regular bumps and nodules, wart-like thickenings, stric-turing lesions, and broad-based masses. In the literature,until recently both adenoma-like and nonadenoma-likeDALMs were often referred to simply by the termDALM without regard to their endoscopic appearance.Nonadenoma-like and adenoma-like DALMs are bestdifferentiated on the basis of their endoscopic featuresbecause there is much overlap in the histologic, immu-

nohistochemical, and molecular features between these 2types of lesions.Nonadenoma-like DALMs represent a heterogeneous

group of dysplastic lesions that have been shown to havea strong positive association with synchronous and meta-chronous carcinoma. In fact, in many instances, biopsy specimens of these lesions simply represent the surface of an underlying carcinoma. The association of cancer withnonadenoma-like DALMs ranges from 38% to 83% inseveral retrospective cohort studies.

In contrast, adenoma-like DALMs represent well-cir-cumscribed dysplastic lesions that appear endoscopically and pathologically similar to sporadic adenomas. Therehave been several retrospective case-control studiesdesignedspecically to evaluate features that may help differentiateIBD-related adenoma-like DALMs from sporadic adenomasby histologic, immunohistochemical, or molecular meth-ods. Although some features, such as young age at diagno-sis, longer duration of disease, prominent villous architec-ture, a mixture of normal and dysplastic epithelium at thesurface of the polyp, bottom-up as opposed to top-down dysplasia, increased inammation in the polyp, pres-ence of stalk dysplasia, and a high frequency of p53 and a low frequency of KRAS mutations, have been shown tobe associated with IBD-related adenoma-like DALMs,

none have proven to be specic enough to be used inindividual patients. If the surrounding at mucosa adja-cent to the dysplastic polyp also shows at dysplasia, theadenoma-like DALM is more likely considered IBD re-lated. This is based on the presumption that dysplasia inUC arises as a generalized eld effect.

Adenoma-like DALMs that occur outside, or proximalto, areas of mucosa involved with inammatory diseaseare considered sporadic in origin and can be managedconservatively with polypectomy under the strong pre-sumption that neoplasia in IBD arises only in areas of chronically inamed mucosa. Patients with IBD and an

adenoma-like DALM within an area of inammatory disease may be treated adequately by polypectomy and

continued surveillance if there is no evidence of atdysplasia in adjacent mucosa, regardless of the underly-ing pathogenesis (whether IBD related or sporadic). Sev-eral prospective studies have conrmed an extremely low rate of dysplasia and/or cancer in patients with IBD and

an adenoma-like DALM, ranging from 0 to 4.6%. Theoutcome of patients with UC or CD and an adenoma-likeDALM is similar regardless of the degree of dysplasia inthe polyp. Therefore, based on these retrospective andprospective studies, there is good evidence to support theconcept that nonsurgical treatment of adenoma-likeDALMs in IBD by polypectomy and continued surveil-lance is a safe approach if there is no evidence of atdysplasia elsewhere in the colon.

Should Colectomy Be Performed forFlat Dysplasia?

Grade A: There is high certainty that colectomy forat HGD treats undiagnosed synchronous cancerand prevents metachronous cancer.

Grade Insufcient: The current evidence is insuf-cient to assess the balance of benets and harmsof colectomy for at LGD.

Flat dysplasia is a term that has been applied tolesions that are not raised, minimally raised, or sometimesinvisible. Not all studies have clearly dened what is meantby at dysplasia, making comparisons between studiessomewhat difcult. With this caveat in mind, if at dyspla-sia is identied within colitic mucosa, unless it can besuccessfully and completely removed endoscopically, strongconsideration should be given to colectomy as the treat-ment of choice. Regarding patients with at HGD, synchro-nous CRC may be present in 42% to 67% of cases. If imme-diate colectomy is not performed in patients with HGDwhen rst detected, CRC develops in 25% to 32% of patientson long-term follow-up. Therefore, although the evidence isconsidered to be of fair quality due to its retrospectivenature, there is generalconsensus among experts in theeldthat colectomy is recommended for patients with at HGD.

The management of patients with LGD is more con-troversial. There is an approximate 19% to 27% prevalencerate of synchronous CRC in patients who have under-gone colectomy within a few months of colonoscopy thatonly showed LGD as the most advanced histologic ab-normality. One recent meta-analysis revealed that thepositive predictive value for progression to HGD and/orCRC from LGD is about 18%. However, signicant vari-ability in progression to HGD or CRC has been notedbetween various studies. Some reveal a progression rateof LGD to advanced neoplasia (HGD or cancer) that

ranges from as low as 0 to 3% over 10 years to 35% to 54%over 5 years.

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Thus, the decision to undergo colectomy versus contin-ued surveillance in the setting of at LGD should be individualized and discussed at length among the patient, thegastroenterologist, and the colorectal surgeon. For instance,if at LGD is detected in biopsy specimens on more than

one occasion, is multifocal (detected at more than one sitein the colon), or is found at the time of initial screeningcolonoscopy (prevalent dysplasia), stronger considerationshould be given to recommending colectomy. Once again, a pathologist with particular expertise in gastrointestinal pa-thology should review all biopsy specimens diagnosed ini-tially as indenite, LGD, or HGD.

Is There Sufcient Rationale forPerforming Surveillance Colonoscopyin Patients With IBD?

Grade B: There is moderate certainty that surveil-lance colonoscopy results in at least moderate re-duction of CRC risk in patients with IBD.

I. Despite the lack of randomized controlled trials, sur-veillance colonoscopy is recommended for patients withIBD at increased risk for developing CRC.

II. Patients with extensive UC or CD of the colon are mostlikely to benet from surveillance.

Proof that surveillance colonoscopy is effective inpatients with IBD requires demonstration of a reduction inmortality due to CRC. Randomized controlled trials testingsurveillance colonoscopy have not been performed. In ad-dition, randomized trials are not likely to be performedbecause of ethical issues related to withholding surveillancefrom a control group and the long duration of follow-upneeded to demonstrate a survival advantage. Nevertheless, a large number of case series and 3 case-control studies havesuggested clinical benet of surveillance colonoscopy forpatients with IBD. However, the Cochrane Group per-formed a pooled analysis of published studies in patientswith UC and concluded that there is no clear evidence that

surveillance colonoscopy prolongs survival in patients withextensive colitis. There was evidence that cancers tended tobe detected at an earlier stage in patients who had under-gone surveillance, and had a better prognosis, compared topatients who had not undergone surveillance. One impor-tant limitation of the studies was the potential for lead-timebias to contribute to the apparent benet of surveillancecolonoscopy. Thus, there is indirect evidence that surveil-lance is effective at reducing the risk of death from IBD-associated CRC.

In balance, patients should be advised that surveillancecolonoscopy offers a reasonable chance of detecting dyspla-

sia or early-stage CRC. Patients with ulcerative proctitis,ulcerative proctosigmoiditis, or limited Crohns colitis do

not require surveillance colonoscopy but should follow age-specic guidelines for CRC screening.

How Should Surveillance ColonoscopyBe Performed?

I. The technique of surveillance colonoscopy in patientswith IBD should include extensive biopsies of all an-atomic segments of colorectal mucosa.

II. Although there are inadequate data available to rec-ommend optimal surveillance intervals, intervals of 1to 3 years are suggested.

III. Careful inspection of the mucosa along with a sufcientnumber of biopsy specimens should be obtained from allanatomic segments of the colon.

To date, our understanding of the efcacy of surveil-lance colonoscopy is based on studies that used random biop-sies of colorectal mucosa, with targeted biopsies only if suspi-cious lesions were noted at endoscopy. Recommendationsregarding the preferred method of performing surveillancecolonoscopy are also based largely on the opinion of interna-tional IBD experts. Surveillance colonoscopy is performed in a rather inconsistent manner by physicians worldwide. Onestudy suggested that to detect dysplasia and/or cancer, rigor-ous surveillance colonoscopy must be performed, includingthe acquisition of at least 33 random biopsy specimens from

all portions of the colon in patients with pancolitis. Becausedysplasia and cancer are more common in the left colon, it isalso recommended that more extensive sampling should beperformedin theleft colon andparticularly therectum. Biopsy specimensshouldalso be obtainedseparately from areas ofatmucosa surrounding the base of adenoma-like and nonade-noma-likeDALMs.Equally important to obtaininga sufcientnumber of biopsy specimens is careful visual inspection of thecolorectal mucosa during colonoscopy.

Chromoendoscopy, or other image-enhancing tech-niques, are recommended for physicians with experiencewith these techniques. With theuse of enhanced endoscopictechniques, targeted biopsies may be performed as an alter-native to obtaining random biopsy specimens (see the nextsection). Poor adherence of patients to their surveillanceprogram reduces the effectiveness of surveillance. The cur-rently recommended guidelines regarding surveillancecolonoscopy are summarized as follows:

1. All patients, regardless of the extent of disease at initialdiagnosis, should undergo a screening colonoscopy a maximum of 8 years after onset of symptoms, withmultiple biopsy specimens obtained throughout the en-tire colon to assess the true microscopic extent of inam-mation.

2. Patients with ulcerative proctitis or ulcerative proctosig-moiditis are not considered at increased risk for IBD-



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related CRC and thus may be managed on the basis of average-risk recommendations.

3. Patients with extensive or left-sided colitis should beginsurveillance within 1 to 2 years after the initial screeningendoscopy.

4. The optimal surveillance interval has not been clearly dened. After 2 negative examinations (no dysplasia orcancer), further surveillance examinations should be per-formedevery 1 to 3 years. Recent data suggests that increas-ing the frequency of surveillance colonoscopy to every 1 to2 years after 20years ofdisease is not neededfor all patientsbut should be individualized according to the presence orabsence of other risk factors (see the next section).

5. There are no prospective studies that have determinedthe optimal number of biopsy specimens that should beobtained to detect dysplasia reliably. Representative bi-opsy specimens from each anatomic section of the colonshould be obtained. One study has recommended that a minimum of 33 biopsy specimens be taken in patientswith pancolitis.

6. Because the sensitivity for detecting dysplasia by chro-moendoscopy is higher than that of white light endos-copy, chromoendoscopy with targeted biopsies is recom-mended as an alternative to random biopsies forendoscopists who have expertise with this technique (seethe next section).

7. Patients with PSC should begin surveillance colonoscopy at the time of this diagnosis and then undergo yearly colonoscopy thereafter.

8. Ideally, surveillance colonoscopy should be performedwhen the colonic disease is in remission.

9. Patients with a history of CRC in rst-degree relatives,ongoing active endoscopic or histologic inammation,or anatomic abnormalities such as a foreshortened colon,stricture, or multiple inammatory pseudopolypsmayben-et from more frequent surveillance examinations.

10. These recommendations also apply to patients withCrohns colitis who have disease involving at least onethird of the length of the colon.

What Role Do the Newer ImagingTechniques Play in Identifying andManaging Dysplasia?

I. The sensitivity of chromoendoscopy for detecting dyspla-sia is higher than white light endoscopy in the hands of endoscopists who have expertise with this technique.

II. The natural history of chromoendoscopically detecteddysplasia is unknown.

III. Additional studies are needed to evaluate the efciency of other imaging methods, such as narrow band imagingand confocal endomicroscopy, in detecting dysplasia.

Several imaging modalities, such as chromoendos-copy with methylene blue or indigo carmine, narrow band

imaging, and confocal endomicroscopy, are currently beingstudied as potential alternatives to white light endoscopy.Several randomized studies suggest that chromoendoscopy increases the yield of detecting dysplasia and may obviatethe need for multiple random biopsies. However, despite

improved detection methods of dysplastic lesions, in in-stances wherecolectomy has been performed based on chro-moendoscopy ndings, unexpected cancers have not yetbeen reported. The performance of chromoendoscopy issubject to the skill of the endoscopist. In addition, high-denition technology and enhanced magnication, is ren-dering white light colonoscopy more accurate in detectingdysplasia. Thus, at this time, normal white light colonos-copy, using standard or high-denition colonoscopes alongwith multiple colon biopsies, remains a reasonable methodof surveillance for patients with IBD. However, chromoen-doscopy with targeted biopsies is considered an acceptablealternative to white light endoscopy for endoscopists whohave experience with this technique. Training issues and thetime required for surveillance examinations need to be ad-dressed carefully before chromoendoscopy is to be consid-ered the new standard method of endoscopic surveillance.Consideration should be given to referring selected high-risk patients to experts who specialize in the performance of enhanced endoscopic imaging techniques for surveillance.

Should Chemopreventive Agents BeUsed to Lower the Risk of Developing

Dysplasia or CRC in IBD?

Grade A: High certainty that the magnitude of net ben-ets is substantial.

I. Ursodeoxycholic acid has demonstrated a signicant reductionin CRC in patients with UC who also have PSC.

Grade B: Moderate certainty that the magnitude of netbenets is moderate.

I. Aminosalicylates are chemopreventive against CRC.

Grade D: High certainty that the magnitude of netbenets is negative.

I. Oral or topical corticosteroids, while demonstrating antineo-plastic effects in 2 studies, are associated with too many sideeffects to warrant use as chemopreventive agents.

Grade Insufcient: No recommendation, insufcientevidence to recommend for or against the use of thio-purines, supplements, or statins.

I. Azathioprine or 6-mercaptopurine has not been consistentlyassociated with lower rates of CRC.

II. Folic acid supplements, calcium, multivitamins, or statinshavenot been consistently associated with lower rates of CRC.



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Chemopreventive agents that have been studied inIBD include aminosalicylates (mesalamine), corticosteroids,immunomodulators, folic acid, and ursodeoxycholic acid(UDCA). Unfortunately, there are no prospective, random-ized, controlled trials that have evaluated the utility of

chemopreventive agents in decreasing the risk of CRC inpatients with IBD. Given the large number of patientsneeded to perform these types of studies, they are not likely to be performed in the near future. With the exception of 2prospective studies of UDCA in patients with UC who alsohave PSC, all other studies of chemopreventive agents havebeen retrospective in design, with a few studies drawingtheir conclusions from population-based registries or phar-maceutical databases. Studies also vary as to whether theend point of the study is CRC, versus HGD or CRC. Fur-thermore, in some recent studies, the type of chemopreven-tive agent was not the primary variable under study.

UDCA is commonly used in patients with UC who alsohave PSC. Indeed, these patients are known to be amongthose with the highest risk of CRC. There is strongevidence that UDCA has a chemopreventive effect againstCRC. However, there is insufcient evidence to determinewhether UDCA also has chemopreventive activity in pa-tients with UC who do not have PSC.

Mesalamine compounds have been shown to have a che-mopreventive effect in many, but not all, studies. For in-stance, one meta-analysis demonstrated a preventive effectof mesalamine for CRC (odds ratio, 0.51; 95% CI, 0.370.69)and for patients with dysplasia and CRC (odds ratio, 0.51;95% CI, 0.38 0.69). The benet occurred with either regularuse of mesalamine compounds or by use of at least 1.2g/day of mesalamine equivalents. In this meta-analysis, useof mesalamine was not signicantly associated with a lowerrisk of dysplasia (odds ratio, 1.18; 95% CI, 0.413.43), butonly 2 studies evaluated dysplasia as an end point. Moststudies have noted that sulfasalazine appears to have a lessprotective effect compared with mesalamine.

Corticosteroid use has been analyzed in several studies,most of which did not nd a chemopreventive effect, al-though details regarding dose and duration were not avail-able. Two studies reported that systemic corticosteroids,and to a lesser extent topical corticosteroids, resulted in a

signicant reduction of CRC risk. At this point, chroniccorticosteroid use is not recommended solely for the pur-pose of chemoprevention due to its toxicity.

Little is known regarding the chemopreventive effects of long-term use of immunomodulators (particularly azathio-prine and 6-mercaptopurine). However, because these drugsrepresent the cornerstone of maintenance therapy, their usein clinical practice is not in question. No study, except one,has examined these agents as a primary variable in theassessment of CRC risk in IBD. In the one study thatspecically evaluated the efcacy of immunomodulators inreducing the risk of CRC, a protective effect of these agents

on the risk of progression to dysplasia or CRC was notdetected.

Four studies evaluated folate use in IBD, 2 of whichanalyzed its use as a primary variable. These studiessuggested a trend toward protection against CRC infolate users, but neither study demonstrated statisticalsignicance. No study has specically analyzed a possible

chemopreventive role for calcium, multivitamins, orstatins. Thus there is insufcient evidence, either for oragainst, the use of these agents for prevention of neopla-sia in patients with IBD at this time.

Should Molecular Markers Be Appliedto Help Stratify Patients Into Low-Risk and High-Risk Groups?

Grade Insufcient: No recommendation; insuf-cient evidence to recommend for or against the useof molecular markers.I. Molecular markers should not be applied to help stratify

patients into low-risk and high-risk groups at this time.

The 3 major molecular pathways of colon carci-nogenesis (chromosomal instability, microsatellite insta-bility, and CpG island methylation pathway) also occurin colitis-associated CRC. Much of the data regardingtypes of molecular alterations in colitis-associated CRChave been obtained from cross-sectional studies that eval-

uated a particular molecular marker of interest at only one point in time, studying lesions that represent thepathological spectrum of neoplasia (no dysplasia, indef-inite for dysplasia, LGD, HGD, and CRC). In these stud-ies, a genetic alteration that demonstrated preferential, orincreased, expression in neoplastic tissue was considereda potentially useful marker of neoplasia. However, few markers have been evaluated prospectively, or chronolog-ically, to determine whether they can predict the simul-taneous occurrence, or subsequent risk, of dysplasia orCRC. Four tissue-based markers (aneuploidy, p53, mic-rosatellite instability, and the mucin-associated sialyl-Tn

antigen) have been evaluated in a chronological context,and each has shown a positive correlation with risk of developing dysplasia or CRC. Of these markers, aneu-ploidy has been the most thoroughly investigated. Severalstudies suggest that aneuploidy occurs diffusely through-out the colon and it usually (but not always) eitherprecedes, or develops synchronously with, dysplasia.However, evaluation of aneuploidy by ow cytometry requires considerable technical and professional exper-tise, which limits its use in routine practice. At this time,there is insufcient evidence to recommend for, oragainst, the use of any other tissue, serum, or stool-based

biomarker in the evaluation of risk of dysplasia or CRCin patients with IBD.



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FRANCIS A. FARRAYE Section of GastroenterologyBoston Medical Center Boston University School of MedicineBoston, Massachusetts

ROBERT D. ODZE Department of PathologyBrigham and Womens Hospital Harvard Medical School Boston, Massachusetts

JAYNE EADEN Department of GastroenterologyUniversity Hospital Coventry, England

STEVEN H. ITZKOWITZThe Dr Henry D. Janowitz Division of Gastroenterology Department of Medicine Mount Sinai School of Medicine New York, New York

In Collaboration With the AGA Institute Medical Position Panel on Diagnosis and Management of Colorectal Neoplasia in Inammatory Bowel Disease

Reference1. Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review

on the diagnosis and management of colorectal neoplasia in in-ammatory bowel disease. Gastroenterology 2010;138:746774.

Reprint requestsAddress requests for reprints to: Chair, Clinical Practice and

Quality Management Committee, AGA National Ofce, 4930 Del RayAvenue, Bethesda, Maryland 20814. Phone: (301) 272-1189;e-mail: [email protected] .

Conicts of interest The authors disclose the following: Dr Farraye has received

research support from Prometheus Laboratories; is a consultant anda member of the speakers bureau for Abbott, Centocor, Proctor &Gamble, Prometheus Laboratories, Salix, and Shire; and is aconsultant for UCB. The remaining authors disclose no conicts.

mailto:[email protected]:[email protected]:[email protected]

Download - AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease

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