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GASTROENTEROLOGY 2010;138:738 –745

AGA

AGA Medical Position Statement on the Diagnosis and Management of


Colorectal 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 Economics
Committee (Joel V. Brill, MD, Predictive Health, LLC).

Are Patients With IBD at Increased


Podcast interview: www.gastro.org/gastropodcast. Risk for Colorectal Cancer?

I n this medical position statement, a series of questions


were identified that are relevant for clinicians who man-
age patients with inflammatory bowel disease (IBD) at risk
I. Patients with ulcerative colitis and Crohn’s disease of the
colon have an increased risk of developing colorectal cancer.
for colorectal neoplasia (Table 1). For each question, a
comprehensive literature search was conducted, pertinent
evidence was reviewed, and the quality of relevant data was Patients with IBD have an increased risk of devel-
evaluated. The details of the methodology used for the oping colorectal cancer (CRC). The exact magnitude of
literature search associated with answering each of the ques- the risk is uncertain due to wide variations in risk re-
tions appear in the following text. The conclusions were ported in many studies. Variations occur because some
based on the best available evidence or, in the absence of studies reported data only from tertiary referral centers,
quality evidence, the expert opinion of the authors of the some were population based, and others represented only
technical review1 and the medical position statement. Some case reports or small series. Meta-analyses have been
of the conclusions constitute recommendations for preven- performed in both patients with ulcerative colitis (UC)
tion. The strength of these recommendations was weighed and patients with Crohn’s disease (CD).
using the US Preventive Services Task Force (USPSTF) From one large meta-analysis, the risk of cancer in pa-
grades, which are detailed in Table 2. tients with UC is estimated at 2% after 10 years, 8% after 20
years, and 18% after 30 years of disease. Data from a UK
Literature Search Methodology 30-year surveillance program calculated the risk of cancer
and dysplasia to be 7.7% at 20 years and 15.8% at 30 years.
A search of the MEDLINE database was performed
Subsequent population-based studies have suggested that
to identify relevant English language articles published in
the risk may not be this high and that the risk has actually
peer-reviewed journals. For this search, the terms dysplasia,
colorectal cancer, surveillance, polyp, chemoprevention, decreased over time. This may be due to widespread use of
chromoendoscopy, endoscopy, primary sclerosing cholangi- aminosalicylates, which are believed to have a chemoprotec-
tis, risk factors, and children were searched in combination tive effect, or to more liberal and early use of colectomy for
with the terms ulcerative colitis, Crohn’s disease, Crohn’s medically refractory disease in some centers, and possibly
colitis, colitis, or inflammatory bowel disease. A manual surveillance colonoscopy.
AGA

search of the reference lists from the potentially relevant


papers was performed to identify additional studies that Abbreviations used in this paper: CI, confidence interval; CRC, colo-
may have been missed using the computer-assisted strategy. rectal carcinoma; DALM, dysplasia-associated lesion or mass; HGD,
high-grade dysplasia; LGD, low-grade dysplasia; PSC, primary scleros-
In most instances, the pathology studies represented retro-
ing cholangitis; USPSTF, US Preventive Services Task Force.
spective case-control, or cohort studies, descriptive studies, © 2010 by the AGA Institute
reports of expert committees, or opinions of respected au- 0016-5085/10/$36.00
thorities in pathology practice. doi:10.1053/j.gastro.2009.12.037
February 2010 AGA 739

Table 1. Questions Relevant for Clinicians Who Manage Extent of disease is also a major risk factor for CRC in
Patients With IBD at Risk for Colorectal Neoplasia patients with IBD. Most cancers arise in patients with
1. Are patients with IBD at increased risk for colorectal cancer? pancolitis. There is an intermediate risk for patients with
2. Are there well-substantiated factors other than dysplasia that left-sided disease (disease up to the splenic flexure),
increase or decrease the risk of CRC in IBD? whereas patients with proctitis or ulcerative proctosig-
3. What is the natural history of dysplasia?
moiditis have either little or no increased risk of CRC.
4. Should colectomy be performed for raised dysplasia?
5. Should colectomy be performed for flat dysplasia? Extent of disease is defined by the most extensive disease
6. Is there sufficient rationale for performing surveillance identified at any time histologically. A colonoscopy is
colonoscopy in patients with IBD? advised after 8 years of disease to redefine the extent of
7. How should surveillance colonoscopy be performed? disease and to decide on subsequent surveillance inter-
8. What role do the newer imaging techniques play in identifying
and managing dysplasia?
vals. Two studies have examined backwash ileitis as
9. Should chemopreventive agents be used to lower the risk of an independent risk factor for development of CRC.
developing dysplasia or CRC in IBD? These studies showed contrasting results. Thus, at
10. Should molecular markers be applied to help stratify patients present, there is insufficient evidence to consider back-
into low- and high-risk groups? wash ileitis as an independent risk factor for CRC in
patients with IBD.
There is good evidence showing that primary scleros-
In CD, there has also been wide variation in the reported ing cholangitis (PSC) is associated with an increased risk
risk of CRC due to inconsistencies in studies. For instance, of CRC. From one meta-analysis, the risk of CRC was
some studies only included patients with small bowel dis- calculated to be increased 4-fold compared to patients
ease and colonic resections, and others did not account for with UC but without PSC. The increased risk was shown
duration of disease. Two meta-analyses that adjusted for to persist after liver transplantation, at a rate of 1% per
these factors have reported the standardized incidence ratio person per year. Patients with PSC may have subclinical
for CRC as 2.5 (95% confidence interval [CI], 1.7–3.5) and UC for many years before their diagnosis of PSC. Thus,
the relative risk (RR) as 4.5 (95% CI, 1.3–14.9). Studies that patients with UC (or Crohn’s colitis) and PSC are recom-
included patients with both UC and CD have shown the mended to commence annual colonoscopy from the time
risk to be roughly equivalent in both diseases (RR of 2.75 of diagnosis of PSC and are also recommended to con-
and 2.64, respectively). In addition, many of the character- tinue surveillance after (possible) liver transplantation.
istics of CRC in UC and CD have been shown to be similar. A positive family history of sporadic CRC in a first-
Thus, extensive Crohn’s colitis should raise the same con- degree relative of a patient with IBD doubles the risk of
cerns regarding CRC risk as UC.

Are There Well-Substantiated Factors Table 2. USPSTF Recommendations and Grades


Other Than Dysplasia That Increase or Strength of recommendations:
Decrease the Risk of CRC in IBD? Grade A indicates that the certainty of evidence is high that the
magnitude of net benefits is substantial. The USPSTF
recommends providing the service for the specific population.
I. Disease duration, more extensive disease, primary scleros- Grade B indicates that the certainty of evidence is moderate that
ing cholangitis, and a positive family history of sporadic the magnitude of net benefits is either moderate or
CRC are all associated with an increased risk of CRC. substantial, or that the certainty of evidence is high that the
magnitude of net benefits is moderate. The USPSTF
II. Colonic strictures in patients with UC and/or a short- recommends providing the service for the specific population.
ened colon, and/or multiple postinflammatory pseu- Grade C indicates that the certainty of the evidence is either high
dopolyps increase the risk of CRC. or moderate that the magnitude of net benefits is small. The
III. Inflammation is a risk factor for progression to colo- USPTF recommends against routinely providing the service for
rectal neoplasia. the specific population. There may be considerations that
support providing the service in an individual patient.
Grade D indicates that the certainty of the evidence is high or
moderate that the magnitude of net benefits is either zero or
Increasing duration of disease is firmly established negative. The USPSTF recommends against providing the
as one of the most important risk factors for the develop- service for the specific population.
Grade I indicates that the evidence is insufficient to determine
ment of CRC in patients with IBD. The risk of CRC is
the relationship between benefits and harms (ie, net benefit).
significant after 8 years of disease and increases in subse- The USPSTF concludes that the current evidence is insufficient
quent years. A small proportion of cancers may arise before to assess the balance of benefits and harms of the service in
8 years, but because this is so infrequent, it does not justify the specific population.
commencing surveillance earlier than 8 years. Rather, it is US Preventive Services Task Force Procedure Manual. AHRQ
Publication No. 08-05118-EF, July 2008. Available at: http://
more appropriate to focus surveillance on patients who
www.ahrq.gov/clinic/uspstf08/methods/procmanual.htm.
have a higher risk as a result of other risk factors.
740 AGA GASTROENTEROLOGY Vol. 138, No. 2

CRC. The risk increases 9-fold if the first-degree relative What Is the Natural History of Dysplasia?
was younger than 50 years of age at the time of diagnosis
of CRC. A positive family history should be regarded as
an important independent risk factor, but it is not yet I. In most cases, CRC in IBD develops from dysplasia.
clear whether this variable should influence surveillance II. Although imperfect, dysplasia is currently considered the
intervals. best marker of CRC risk in IBD.
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 but Dysplasia is currently considered the best marker
histologically active colitis. CRC can also occur in areas of CRC risk in IBD, but there are limitations in predict-
where active colitis has remitted, that is, areas where ing the natural history of dysplasia. Although dysplasia is
there is no active inflammation but where there may be present in 75% to 90% of patients with cancer, CRC can
histologic findings of inactive colitis, such as crypt dis- develop in patients without a prior history of dysplasia.
tortion. Lack of endoscopic inflammation at the time of Also, not all patients with low-grade dysplasia (LGD) will
detection of neoplasia does not mean that there was an progress through a phase of detectable high-grade dys-
plasia (HGD) before developing cancer. Importantly, the
absence of inflammation in the area of neoplasia before
interpretation of dysplasia in mucosal biopsy specimens
its development. The risk of neoplasia is not increased in
is subject to a high level of interobserver variability. Thus,
mucosa that has never been inflamed. Thus, histologic
pathologists with particular expertise in gastrointestinal
rather than macroscopic changes of disease are a better
disorders should review all cases diagnosed as indefinite,
determinant of the presence or absence of inflammation
LGD, or HGD. Until more reliable markers of cancer risk
for the purpose of assessing cancer risk. For the purpose
are identified, clinical management depends on the en-
of surveillance, extent of disease should be defined his-
doscopic and histologic identification of dysplasia in
tologically. For example, a patient with evidence of en- mucosal biopsy specimens of the colon. In patients found
doscopic disease up to 10 cm but with active or chronic to have dysplasia on one colonoscopy, the absence of
inflammation (or documented evidence of previous in- dysplasia on follow-up colonoscopy does not provide
flammation) up to 60 cm documented histologically, reassurance that the risk of CRC has declined. Patients
should be surveyed as if he or she has left-sided colitis with biopsy specimens that show indefinite dysplasia
and not proctitis. have a risk of progression to HGD or CRC higher than in
It has been reported that strictures, especially in UC, patients without dysplasia. Unifocal low-grade dysplasia
and the presence of a shortened colon (representing long- has been shown to carry a similar risk of CRC as multi-
standing inflammation) are associated with an increased focal dysplasia in one study, but this remains to be
risk of CRC. Extra vigilance is required by the colonos- confirmed in other studies.
copist in patients with any of these features, and extra
biopsies are highly recommended. Multiple postinflam- Should Colectomy Be Performed for
matory pseudopolyps have been shown to double the risk Raised Dysplasia?
of CRC. Surveillance may have reduced benefit in the
context of multiple pseudopolyps, and thus affected pa-
tients should be made aware of this limitation. Some Grade A: High certainty that the magnitude of net
patients may choose prophylactic colectomy over contin- benefits is substantial.
ued surveillance in this circumstance. I. Patients with IBD and a non–adenoma-like dysplasia-
Early age at onset of IBD symptoms has not been associated lesion or mass should be treated with colectomy.
consistently shown to represent an independent risk fac- II. Patients with IBD and an adenoma-like dysplasia-associ-
tor of CRC. It has been reported that the cumulative risk ated lesion or mass, and no evidence of flat dysplasia
of CRC in patients with extensive UC is 40% in whom the elsewhere in the colon, can be managed safely by polypec-
disease began before 15 years of age and 25% in patients tomy and continued surveillance.
who develop UC between 15 and 39 years of age. Other
data that suggest an increased risk of CRC in patients
with IBD diagnosed after the age of 40 years may reflect Raised, endoscopically visible, dysplastic lesions in
a contribution from the age-related risk of developing IBD have been referred to by the acronym “DALM” (dys-
sporadic CRC. Children diagnosed with IBD have at least plasia-associated lesion or mass). Recent studies suggest
an equivalent rate of CRC development compared to that IBD-related DALMs may be broadly separated into
patients diagnosed at an older age. Thus, surveillance those that appear similar to sporadic adenomas in non-
should be conducted as frequently in children as in IBD patients, referred to as adenoma-like DALMs, and
adults and should be based on duration of disease, not those that do not resemble adenoma-like DALMs, which
chronological age. are referred to as non–adenoma-like DALMs. Both types
February 2010 AGA 741

of DALMs are typically composed of dysplastic columnar continued surveillance if there is no evidence of flat
cells that resemble those of sporadic neoplasia. Adeno- dysplasia in adjacent mucosa, regardless of the underly-
ma-like DALMs represent well-circumscribed, smooth or ing pathogenesis (whether IBD related or sporadic). Sev-
papillary nonnecrotic, sessile or pedunculated polyps that eral prospective studies have confirmed an extremely low
are usually readily accessible to removal by routine endo- rate of dysplasia and/or cancer in patients with IBD and
scopic methods. Other synonyms used to describe this le- an adenoma-like DALM, ranging from 0 to 4.6%. The
sion include adenoma-like polyp, adenoma-like dysplastic outcome of patients with UC or CD and an adenoma-like
polyp, polypoid dysplasia, and adenoma-like mass. Non– DALM is similar regardless of the degree of dysplasia in
adenoma-like DALMs include velvety patches, plaques, ir- the polyp. Therefore, based on these retrospective and
regular bumps and nodules, wart-like thickenings, stric- prospective studies, there is good evidence to support the
turing lesions, and broad-based masses. In the literature, concept that nonsurgical treatment of adenoma-like
until recently both adenoma-like and non–adenoma-like DALMs in IBD by polypectomy and continued surveil-
DALMs were often referred to simply by the term lance is a safe approach if there is no evidence of flat
“DALM” without regard to their endoscopic appearance. dysplasia elsewhere in the colon.
Non–adenoma-like and adenoma-like DALMs are best
differentiated on the basis of their endoscopic features Should Colectomy Be Performed for
because there is much overlap in the histologic, immu- Flat Dysplasia?
nohistochemical, and molecular features between these 2
types of lesions.
Non–adenoma-like DALMs represent a heterogeneous Grade A: There is high certainty that colectomy for
group of dysplastic lesions that have been shown to have flat HGD treats undiagnosed synchronous cancer
a strong positive association with synchronous and meta- and prevents metachronous cancer.
chronous carcinoma. In fact, in many instances, biopsy Grade Insufficient: The current evidence is insuf-
specimens of these lesions simply represent the surface of ficient to assess the balance of benefits and harms
an underlying carcinoma. The association of cancer with of colectomy for flat LGD.
non–adenoma-like DALMs ranges from 38% to 83% in
several retrospective cohort studies.
In contrast, adenoma-like DALMs represent well-cir- “Flat dysplasia” is a term that has been applied to
cumscribed dysplastic lesions that appear endoscopically lesions that are not raised, minimally raised, or sometimes
and pathologically similar to sporadic adenomas. There invisible. Not all studies have clearly defined what is meant
have been several retrospective case-control studies designed by “flat dysplasia,” making comparisons between studies
specifically to evaluate features that may help differentiate somewhat difficult. With this caveat in mind, if flat dyspla-
IBD-related adenoma-like DALMs from sporadic adenomas sia is identified within colitic mucosa, unless it can be
by histologic, immunohistochemical, or molecular meth- successfully and completely removed endoscopically, strong
ods. Although some features, such as young age at diagno- consideration should be given to colectomy as the treat-
sis, longer duration of disease, prominent villous architec- ment of choice. Regarding patients with flat HGD, synchro-
ture, a mixture of normal and dysplastic epithelium at the nous CRC may be present in 42% to 67% of cases. If imme-
surface of the polyp, “bottom-up” as opposed to “top- diate colectomy is not performed in patients with HGD
down” dysplasia, increased inflammation in the polyp, pres- when first detected, CRC develops in 25% to 32% of patients
ence of stalk dysplasia, and a high frequency of p53 and a on long-term follow-up. Therefore, although the evidence is
low frequency of KRAS mutations, have been shown to considered to be of fair quality due to its retrospective
be associated with IBD-related adenoma-like DALMs, nature, there is general consensus among experts in the field
none have proven to be specific enough to be used in that colectomy is recommended for patients with flat HGD.
individual patients. If the surrounding flat mucosa adja- The management of patients with LGD is more con-
cent to the dysplastic polyp also shows flat dysplasia, the troversial. There is an approximate 19% to 27% prevalence
adenoma-like DALM is more likely considered IBD re- rate of synchronous CRC in patients who have under-
lated. This is based on the presumption that dysplasia in gone colectomy within a few months of colonoscopy that
UC arises as a generalized field effect. only showed LGD as the most advanced histologic ab-
Adenoma-like DALMs that occur outside, or proximal normality. One recent meta-analysis revealed that the
to, areas of mucosa involved with inflammatory disease positive predictive value for progression to HGD and/or
are considered sporadic in origin and can be managed CRC from LGD is about 18%. However, significant vari-
conservatively with polypectomy under the strong pre- ability in progression to HGD or CRC has been noted
sumption that neoplasia in IBD arises only in areas of between various studies. Some reveal a progression rate
chronically inflamed mucosa. Patients with IBD and an of LGD to advanced neoplasia (HGD or cancer) that
adenoma-like DALM within an area of inflammatory ranges from as low as 0 to 3% over 10 years to 35% to 54%
disease may be treated adequately by polypectomy and over 5 years.
742 AGA GASTROENTEROLOGY Vol. 138, No. 2

Thus, the decision to undergo colectomy versus contin- not require surveillance colonoscopy but should follow age-
ued surveillance in the setting of flat LGD should be indi- specific guidelines for CRC screening.
vidualized and discussed at length among the patient, the
gastroenterologist, and the colorectal surgeon. For instance,
How Should Surveillance Colonoscopy
if flat LGD is detected in biopsy specimens on more than Be Performed?
one occasion, is multifocal (detected at more than one site
in the colon), or is found at the time of initial screening
colonoscopy (prevalent dysplasia), stronger consideration I. The technique of surveillance colonoscopy in patients
should be given to recommending colectomy. Once again, a with IBD should include extensive biopsies of all an-
pathologist with particular expertise in gastrointestinal pa- atomic segments of colorectal mucosa.
thology should review all biopsy specimens diagnosed ini- II. Although there are inadequate data available to rec-
tially as indefinite, LGD, or HGD. ommend optimal surveillance intervals, intervals of 1
to 3 years are suggested.
Is There Sufficient Rationale for III. Careful inspection of the mucosa along with a sufficient
Performing Surveillance Colonoscopy number of biopsy specimens should be obtained from all
in Patients With IBD? anatomic segments of the colon.

Grade B: There is moderate certainty that surveil- To date, our understanding of the efficacy of surveil-
lance colonoscopy results in at least moderate re- lance colonoscopy is based on studies that used random biop-
duction of CRC risk in patients with IBD. sies of colorectal mucosa, with targeted biopsies only if suspi-
I. Despite the lack of randomized controlled trials, sur- cious lesions were noted at endoscopy. Recommendations
veillance colonoscopy is recommended for patients with regarding the preferred method of performing surveillance
IBD at increased risk for developing CRC. colonoscopy are also based largely on the opinion of interna-
II. Patients with extensive UC or CD of the colon are most tional IBD experts. Surveillance colonoscopy is performed in a
likely to benefit from surveillance. rather inconsistent manner by physicians worldwide. One
study suggested that to detect dysplasia and/or cancer, rigor-
ous surveillance colonoscopy must be performed, including
the acquisition of at least 33 random biopsy specimens from
Proof that surveillance colonoscopy is effective in all portions of the colon in patients with pancolitis. Because
patients with IBD requires demonstration of a reduction in dysplasia and cancer are more common in the left colon, it is
mortality due to CRC. Randomized controlled trials testing also recommended that more extensive sampling should be
surveillance colonoscopy have not been performed. In ad- performed in the left colon and particularly the rectum. Biopsy
dition, randomized trials are not likely to be performed specimens should also be obtained separately from areas of flat
because of ethical issues related to withholding surveillance mucosa surrounding the base of adenoma-like and non–ade-
from a control group and the long duration of follow-up noma-like DALMs. Equally important to obtaining a sufficient
needed to demonstrate a survival advantage. Nevertheless, a number of biopsy specimens is careful visual inspection of the
large number of case series and 3 case-control studies have colorectal mucosa during colonoscopy.
suggested clinical benefit of surveillance colonoscopy for Chromoendoscopy, or other image-enhancing tech-
patients with IBD. However, the Cochrane Group per- niques, are recommended for physicians with experience
formed a pooled analysis of published studies in patients with these techniques. With the use of enhanced endoscopic
with UC and concluded that there is no clear evidence that techniques, targeted biopsies may be performed as an alter-
surveillance colonoscopy prolongs survival in patients with native to obtaining random biopsy specimens (see the next
extensive colitis. There was evidence that cancers tended to section). Poor adherence of patients to their surveillance
be detected at an earlier stage in patients who had under- program reduces the effectiveness of surveillance. The cur-
gone surveillance, and had a better prognosis, compared to rently recommended guidelines regarding surveillance
patients who had not undergone surveillance. One impor- colonoscopy are summarized as follows:
tant limitation of the studies was the potential for lead-time
bias to contribute to the apparent benefit of surveillance 1. All patients, regardless of the extent of disease at initial
colonoscopy. Thus, there is indirect evidence that surveil- diagnosis, should undergo a screening colonoscopy a
lance is effective at reducing the risk of death from IBD- maximum of 8 years after onset of symptoms, with
associated CRC. multiple biopsy specimens obtained throughout the en-
In balance, patients should be advised that surveillance tire colon to assess the true microscopic extent of inflam-
colonoscopy offers a reasonable chance of detecting dyspla- mation.
sia or early-stage CRC. Patients with ulcerative proctitis, 2. Patients with ulcerative proctitis or ulcerative proctosig-
ulcerative proctosigmoiditis, or limited Crohn’s colitis do moiditis are not considered at increased risk for IBD-
February 2010 AGA 743

related CRC and thus may be managed on the basis of imaging, and confocal endomicroscopy, are currently being
average-risk recommendations. studied as potential alternatives to white light endoscopy.
3. Patients with extensive or left-sided colitis should begin Several randomized studies suggest that chromoendoscopy
surveillance within 1 to 2 years after the initial screening increases the yield of detecting dysplasia and may obviate
endoscopy. the need for multiple random biopsies. However, despite
4. The optimal surveillance interval has not been clearly improved detection methods of dysplastic lesions, in in-
defined. After 2 negative examinations (no dysplasia or stances where colectomy has been performed based on chro-
cancer), further surveillance examinations should be per- moendoscopy findings, unexpected cancers have not yet
formed every 1 to 3 years. Recent data suggests that increas- been reported. The performance of chromoendoscopy is
ing the frequency of surveillance colonoscopy to every 1 to subject to the skill of the endoscopist. In addition, high-
2 years after 20 years of disease is not needed for all patients definition technology and enhanced magnification, is ren-
but should be individualized according to the presence or dering white light colonoscopy more accurate in detecting
absence of other risk factors (see the next section).
dysplasia. Thus, at this time, normal white light colonos-
5. There are no prospective studies that have determined
copy, using standard or high-definition colonoscopes along
the optimal number of biopsy specimens that should be
with multiple colon biopsies, remains a reasonable method
obtained to detect dysplasia reliably. Representative bi-
of surveillance for patients with IBD. However, chromoen-
opsy specimens from each anatomic section of the colon
should be obtained. One study has recommended that a doscopy with targeted biopsies is considered an acceptable
minimum of 33 biopsy specimens be taken in patients alternative to white light endoscopy for endoscopists who
with pancolitis. have experience with this technique. Training issues and the
6. Because the sensitivity for detecting dysplasia by chro- time required for surveillance examinations need to be ad-
moendoscopy is higher than that of white light endos- dressed carefully before chromoendoscopy is to be consid-
copy, chromoendoscopy with targeted biopsies is recom- ered the new standard method of endoscopic surveillance.
mended as an alternative to random biopsies for Consideration should be given to referring selected high-
endoscopists who have expertise with this technique (see risk patients to experts who specialize in the performance of
the next section). enhanced endoscopic imaging techniques for surveillance.
7. Patients with PSC should begin surveillance colonoscopy
at the time of this diagnosis and then undergo yearly
colonoscopy thereafter. Should Chemopreventive Agents Be
8. Ideally, surveillance colonoscopy should be performed
Used to Lower the Risk of Developing
Dysplasia or CRC in IBD?
when the colonic disease is in remission.
9. Patients with a history of CRC in first-degree relatives,
ongoing active endoscopic or histologic inflammation,
Grade A: High certainty that the magnitude of net ben-
or anatomic abnormalities such as a foreshortened colon,
efits is substantial.
stricture, or multiple inflammatory pseudopolyps may ben-
efit from more frequent surveillance examinations. I. Ursodeoxycholic acid has demonstrated a significant reduction
10. These recommendations also apply to patients with in CRC in patients with UC who also have PSC.
Crohn’s colitis who have disease involving at least one
Grade B: Moderate certainty that the magnitude of net
third of the length of the colon.
benefits is moderate.
What Role Do the Newer Imaging I. Aminosalicylates are chemopreventive against CRC.
Techniques Play in Identifying and
Managing Dysplasia? Grade D: High certainty that the magnitude of net
benefits is negative.

I. The sensitivity of chromoendoscopy for detecting dyspla- I. Oral or topical corticosteroids, while demonstrating antineo-
sia is higher than white light endoscopy in the hands of plastic effects in 2 studies, are associated with too many side
endoscopists who have expertise with this technique. effects to warrant use as chemopreventive agents.
II. The natural history of chromoendoscopically detected Grade Insufficient: No recommendation, insufficient
dysplasia is unknown. evidence to recommend for or against the use of thio-
III. Additional studies are needed to evaluate the efficiency of purines, supplements, or statins.
other imaging methods, such as narrow band imaging
and confocal endomicroscopy, in detecting dysplasia. I. Azathioprine or 6-mercaptopurine has not been consistently
associated with lower rates of CRC.
II. Folic acid supplements, calcium, multivitamins, or statins
Several imaging modalities, such as chromoendos- have not been consistently associated with lower rates of CRC.
copy with methylene blue or indigo carmine, narrow band
744 AGA GASTROENTEROLOGY Vol. 138, No. 2

Chemopreventive agents that have been studied in Four studies evaluated folate use in IBD, 2 of which
IBD include aminosalicylates (mesalamine), corticosteroids, analyzed its use as a primary variable. These studies
immunomodulators, folic acid, and ursodeoxycholic acid suggested a trend toward protection against CRC in
(UDCA). Unfortunately, there are no prospective, random- folate users, but neither study demonstrated statistical
ized, controlled trials that have evaluated the utility of significance. No study has specifically analyzed a possible
chemopreventive agents in decreasing the risk of CRC in chemopreventive role for calcium, multivitamins, or
patients with IBD. Given the large number of patients statins. Thus there is insufficient evidence, either for or
needed to perform these types of studies, they are not likely against, the use of these agents for prevention of neopla-
to be performed in the near future. With the exception of 2 sia in patients with IBD at this time.
prospective studies of UDCA in patients with UC who also
have PSC, all other studies of chemopreventive agents have
been retrospective in design, with a few studies drawing Should Molecular Markers Be Applied
their conclusions from population-based registries or phar- to Help Stratify Patients Into Low-Risk
maceutical databases. Studies also vary as to whether the and High-Risk Groups?
end 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. Grade Insufficient: No recommendation; insuffi-
cient evidence to recommend for or against the use
UDCA is commonly used in patients with UC who also
of molecular markers.
have PSC. Indeed, these patients are known to be among
those with the highest risk of CRC. There is strong I. Molecular markers should not be applied to help stratify
evidence that UDCA has a chemopreventive effect against patients into low-risk and high-risk groups at this time.
CRC. However, there is insufficient evidence to determine
whether UDCA also has chemopreventive activity in pa-
tients with UC who do not have PSC. The 3 major molecular pathways of colon carci-
Mesalamine compounds have been shown to have a che- nogenesis (chromosomal instability, microsatellite insta-
mopreventive effect in many, but not all, studies. For in- bility, and CpG island methylation pathway) also occur
stance, one meta-analysis demonstrated a preventive effect
in colitis-associated CRC. Much of the data regarding
of mesalamine for CRC (odds ratio, 0.51; 95% CI, 0.37– 0.69)
types of molecular alterations in colitis-associated CRC
and for patients with dysplasia and CRC (odds ratio, 0.51;
have been obtained from cross-sectional studies that eval-
95% CI, 0.38 – 0.69). The benefit occurred with either regular
uated a particular molecular marker of interest at only
use of mesalamine compounds or by use of at least 1.2
one point in time, studying lesions that represent the
g/day of mesalamine equivalents. In this meta-analysis, use
pathological spectrum of neoplasia (no dysplasia, indef-
of mesalamine was not significantly associated with a lower
inite for dysplasia, LGD, HGD, and CRC). In these stud-
risk of dysplasia (odds ratio, 1.18; 95% CI, 0.41–3.43), but
ies, a genetic alteration that demonstrated preferential, or
only 2 studies evaluated dysplasia as an end point. Most
increased, expression in neoplastic tissue was considered
studies have noted that sulfasalazine appears to have a less
protective effect compared with mesalamine. a potentially useful marker of neoplasia. However, few
Corticosteroid use has been analyzed in several studies, markers have been evaluated prospectively, or chronolog-
most of which did not find a chemopreventive effect, al- ically, to determine whether they can predict the simul-
though details regarding dose and duration were not avail- taneous occurrence, or subsequent risk, of dysplasia or
able. Two studies reported that systemic corticosteroids, CRC. Four tissue-based markers (aneuploidy, p53, mic-
and to a lesser extent topical corticosteroids, resulted in a rosatellite instability, and the mucin-associated sialyl-Tn
significant reduction of CRC risk. At this point, chronic antigen) have been evaluated in a chronological context,
corticosteroid use is not recommended solely for the pur- and each has shown a positive correlation with risk of
pose of chemoprevention due to its toxicity. developing dysplasia or CRC. Of these markers, aneu-
Little is known regarding the chemopreventive effects of ploidy has been the most thoroughly investigated. Several
long-term use of immunomodulators (particularly azathio- studies suggest that aneuploidy occurs diffusely through-
prine and 6-mercaptopurine). However, because these drugs out the colon and it usually (but not always) either
represent the cornerstone of maintenance therapy, their use precedes, or develops synchronously with, dysplasia.
in clinical practice is not in question. No study, except one, However, evaluation of aneuploidy by flow cytometry
has examined these agents as a primary variable in the requires considerable technical and professional exper-
assessment of CRC risk in IBD. In the one study that tise, which limits its use in routine practice. At this time,
specifically evaluated the efficacy of immunomodulators in there is insufficient evidence to recommend for, or
reducing the risk of CRC, a protective effect of these agents against, the use of any other tissue, serum, or stool-based
on the risk of progression to dysplasia or CRC was not biomarker in the evaluation of risk of dysplasia or CRC
detected. in patients with IBD.
February 2010 AGA 745

FRANCIS A. FARRAYE In Collaboration With the AGA Institute Medical


Section of Gastroenterology Position Panel on Diagnosis and Management of
Boston Medical Center Colorectal Neoplasia in Inflammatory Bowel Disease
Boston University School of Medicine
Boston, Massachusetts
Reference
ROBERT D. ODZE 1. Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review
Department of Pathology on the diagnosis and management of colorectal neoplasia in in-
Brigham and Women’s Hospital flammatory bowel disease. Gastroenterology 2010;138:746 –
774.
Harvard Medical School
Boston, Massachusetts
JAYNE EADEN Reprint requests
Department of Gastroenterology Address requests for reprints to: Chair, Clinical Practice and
University Hospital Quality Management Committee, AGA National Office, 4930 Del Ray
Coventry, England Avenue, Bethesda, Maryland 20814. Phone: (301) 272-1189;
e-mail: SAgyeman@gastro.org.
STEVEN H. ITZKOWITZ
The Dr Henry D. Janowitz Division of Conflicts of interest
Gastroenterology The authors disclose the following: Dr Farraye has received
research support from Prometheus Laboratories; is a consultant and
Department of Medicine a member of the speaker’s bureau for Abbott, Centocor, Proctor &
Mount Sinai School of Medicine Gamble, Prometheus Laboratories, Salix, and Shire; and is a
New York, New York consultant for UCB. The remaining authors disclose no conflicts.