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
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
evaluated. The details of the methodology used for the
literature search associated with answering each of the ques-
tions appear in the following text. The conclusions were
based on the best available evidence or, in the absence of
quality evidence, the expert opinion of the authors of the
technical review1 and the medical position statement. Some
of the conclusions constitute recommendations for preven-
tion. The strength of these recommendations was weighed
using 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 in
peer-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 combination
with the terms ulcerative colitis, Crohn’s disease, Crohn’s
colitis, colitis, or inflammatory bowel disease. A manual
AGA
I. Patients with ulcerative colitis and Crohn’s disease of the
colon 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 some
studies reported data only from tertiary referral centers,
some were population based, and others represented only
case reports or small series. Meta-analyses have been
performed 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 20
years, and 18% after 30 years of disease. Data from a UK
30-year surveillance program calculated the risk of cancer
and dysplasia to be 7.7% at 20 years and 15.8% at 30 years.
Subsequent population-based studies have suggested that
the 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 for
medically refractory disease in some centers, and possibly
surveillance colonoscopy.

search of the reference lists from the potentially relevant

papers was performed to identify additional studies that
may 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.
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 Institute
0016-5085/10/$36.00
doi:10.1053/j.gastro.2009.12.037
February 2010
Table 1. Questions Relevant for Clinicians Who Manage
Patients 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 that
increase 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 surveillance
colonoscopy in patients with IBD?
7. How should surveillance colonoscopy be performed?
8. What role do the newer imaging techniques play in identifying
and 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 patients
into low- and high-risk groups?
In CD, there has also been wide variation in the reported
risk 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 for
duration of disease. Two meta-analyses that adjusted for
these factors have reported the standardized incidence ratio
for CRC as 2.5 (95% confidence interval [CI], 1.7–3.5) and
the relative risk (RR) as 4.5 (95% CI, 1.3–14.9). Studies that
included patients with both UC and CD have shown the
risk to be roughly equivalent in both diseases (RR of 2.75
and 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 Factors
Other Than Dysplasia That Increase or
Decrease the Risk of CRC in IBD?
I. Disease duration, more extensive disease, primary scleros-
ing cholangitis, and a positive family history of sporadic
CRC 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 established
as one of the most important risk factors for the develop-
ment of CRC in patients with IBD. The risk of CRC is
significant after 8 years of disease and increases in subse-
quent years. A small proportion of cancers may arise before
8 years, but because this is so infrequent, it does not justify
commencing surveillance earlier than 8 years. Rather, it is
more appropriate to focus surveillance on patients who
have a higher risk as a result of other risk factors.
AGA 739
Extent of disease is also a major risk factor for CRC in
patients with IBD. Most cancers arise in patients with
pancolitis. There is an intermediate risk for patients with
left-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 disease
identified at any time histologically. A colonoscopy is
advised 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 as
an independent risk factor for development of CRC.
These studies showed contrasting results. Thus, at
present, there is insufficient evidence to consider back-
wash ileitis as an independent risk factor for CRC in
patients with IBD.
There is good evidence showing that primary scleros-
ing cholangitis (PSC) is associated with an increased risk
of CRC. From one meta-analysis, the risk of CRC was
calculated to be increased 4-fold compared to patients
with UC but without PSC. The increased risk was shown
to persist after liver transplantation, at a rate of 1% per
person per year. Patients with PSC may have subclinical
UC 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 time
of 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 2. USPSTF Recommendations and Grades
Strength of recommendations:
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.
Grade B indicates that the certainty of evidence is moderate that
the magnitude of net benefits is either moderate or
substantial, or that the certainty of evidence is high that the
magnitude 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 high
or moderate that the magnitude of net benefits is small. The
USPTF recommends against routinely providing the service for
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
negative. The USPSTF recommends against providing the
service for the specific population.
Grade I indicates that the evidence is insufficient to determine
the relationship between benefits and harms (ie, net benefit).
The USPSTF concludes that the current evidence is insufficient
to assess the balance of benefits and harms of the service in
the specific population.
US Preventive Services Task Force Procedure Manual. AHRQ
Publication No. 08-05118-EF, July 2008. Available at: http://
www.ahrq.gov/clinic/uspstf08/methods/procmanual.htm.
740 AGA
CRC. The risk increases 9-fold if the first-degree relative
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
clear whether this variable should influence surveillance
intervals.
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
histologically active colitis. CRC can also occur in areas
where active colitis has remitted, that is, areas where
there is no active inflammation but where there may be
histologic 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 an
absence of inflammation in the area of neoplasia before
its development. The risk of neoplasia is not increased in
mucosa that has never been inflamed. Thus, histologic
rather than macroscopic changes of disease are a better
determinant of the presence or absence of inflammation
for the purpose of assessing cancer risk. For the purpose
of 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 chronic
inflammation (or documented evidence of previous in-
flammation) up to 60 cm documented histologically,
should be surveyed as if he or she has left-sided colitis
and 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 increased
risk 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 risk
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
patients 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 risk
of CRC in patients with extensive UC is 40% in whom the
disease began before 15 years of age and 25% in patients
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
a contribution from the age-related risk of developing
sporadic CRC. Children diagnosed with IBD have at least
an equivalent rate of CRC development compared to
patients diagnosed at an older age. Thus, surveillance
should be conducted as frequently in children as in
adults and should be based on duration of disease, not
chronological age.
GASTROENTEROLOGY Vol. 138, No. 2
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 marker
of CRC risk in IBD, but there are limitations in predict-
ing the natural history of dysplasia. Although dysplasia is
present in 75% to 90% of patients with cancer, CRC can
develop in patients without a prior history of dysplasia.
Also, not all patients with low-grade dysplasia (LGD) will
progress through a phase of detectable high-grade dys-
plasia (HGD) before developing cancer. Importantly, the
interpretation of dysplasia in mucosal biopsy specimens
is subject to a high level of interobserver variability. Thus,
pathologists with particular expertise in gastrointestinal
disorders should review all cases diagnosed as indefinite,
LGD, or HGD. Until more reliable markers of cancer risk
are identified, clinical management depends on the en-
doscopic and histologic identification of dysplasia in
mucosal biopsy specimens of the colon. In patients found
to have dysplasia on one colonoscopy, the absence of
dysplasia on follow-up colonoscopy does not provide
reassurance that the risk of CRC has declined. Patients
with biopsy specimens that show indefinite dysplasia
have a risk of progression to HGD or CRC higher than in
patients 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 be
confirmed in other studies.
Should Colectomy Be Performed for
Raised Dysplasia?
Grade A: High certainty that the magnitude of net
benefits is substantial.
I. Patients with IBD and a non–adenoma-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 flat dysplasia
elsewhere in the colon, can be managed safely by polypec-
tomy and continued surveillance.
Raised, endoscopically visible, dysplastic lesions in
IBD have been referred to by the acronym “DALM” (dys-
plasia-associated lesion or mass). Recent studies suggest
that IBD-related DALMs may be broadly separated into
those 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, which
are referred to as non–adenoma-like DALMs. Both types
February 2010
of DALMs are typically composed of dysplastic columnar
cells that resemble those of sporadic neoplasia. Adeno-
ma-like DALMs represent well-circumscribed, smooth or
papillary nonnecrotic, sessile or pedunculated polyps that
are usually readily accessible to removal by routine endo-
scopic methods. Other synonyms used to describe this le-
sion include adenoma-like polyp, adenoma-like dysplastic
polyp, polypoid dysplasia, and adenoma-like mass. Non–
adenoma-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 non–adenoma-like
DALMs were often referred to simply by the term
“DALM” without regard to their endoscopic appearance.
Non–adenoma-like and adenoma-like DALMs are best
differentiated on the basis of their endoscopic features
because there is much overlap in the histologic, immu-
nohistochemical, and molecular features between these 2
types of lesions.
Non–adenoma-like DALMs represent a heterogeneous
group of dysplastic lesions that have been shown to have
a 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 with
non–adenoma-like DALMs ranges from 38% to 83% in
several retrospective cohort studies.
In contrast, adenoma-like DALMs represent well-cir-
cumscribed dysplastic lesions that appear endoscopically
and pathologically similar to sporadic adenomas. There
have been several retrospective case-control studies designed
specifically to evaluate features that may help differentiate
IBD-related adenoma-like DALMs from sporadic adenomas
by 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 the
surface of the polyp, “bottom-up” as opposed to “top-
down” dysplasia, increased inflammation in the polyp, pres-
ence of stalk dysplasia, and a high frequency of p53 and a
low frequency of KRAS mutations, have been shown to
be associated with IBD-related adenoma-like DALMs,
none have proven to be specific enough to be used in
individual patients. If the surrounding flat mucosa adja-
cent to the dysplastic polyp also shows flat dysplasia, the
adenoma-like DALM is more likely considered IBD re-
lated. This is based on the presumption that dysplasia in
UC arises as a generalized field effect.
Adenoma-like DALMs that occur outside, or proximal
to, areas of mucosa involved with inflammatory disease
are considered sporadic in origin and can be managed
conservatively with polypectomy under the strong pre-
sumption that neoplasia in IBD arises only in areas of
chronically inflamed mucosa. Patients with IBD and an
adenoma-like DALM within an area of inflammatory
disease may be treated adequately by polypectomy and
AGA 741
continued surveillance if there is no evidence of flat
dysplasia in adjacent mucosa, regardless of the underly-
ing pathogenesis (whether IBD related or sporadic). Sev-
eral prospective studies have confirmed an extremely low
rate of dysplasia and/or cancer in patients with IBD and
an adenoma-like DALM, ranging from 0 to 4.6%. The
outcome of patients with UC or CD and an adenoma-like
DALM is similar regardless of the degree of dysplasia in
the polyp. Therefore, based on these retrospective and
prospective studies, there is good evidence to support the
concept that nonsurgical treatment of adenoma-like
DALMs in IBD by polypectomy and continued surveil-
lance is a safe approach if there is no evidence of flat
dysplasia elsewhere in the colon.
Should Colectomy Be Performed for
Flat Dysplasia?
Grade A: There is high certainty that colectomy for
flat HGD treats undiagnosed synchronous cancer
and prevents metachronous cancer.
Grade Insufficient: The current evidence is insuf-
ficient to assess the balance of benefits and harms
of colectomy for flat LGD.
“Flat dysplasia” is a term that has been applied to
lesions that are not raised, minimally raised, or sometimes
invisible. Not all studies have clearly defined what is meant
by “flat dysplasia,” making comparisons between studies
somewhat difficult. With this caveat in mind, if flat dyspla-
sia is identified within colitic mucosa, unless it can be
successfully and completely removed endoscopically, strong
consideration should be given to colectomy as the treat-
ment of choice. Regarding patients with flat HGD, synchro-
nous CRC may be present in 42% to 67% of cases. If imme-
diate colectomy is not performed in patients with HGD
when first detected, CRC develops in 25% to 32% of patients
on long-term follow-up. Therefore, although the evidence is
considered to be of fair quality due to its retrospective
nature, there is general consensus among experts in the field
that colectomy is recommended for patients with flat HGD.
The management of patients with LGD is more con-
troversial. There is an approximate 19% to 27% prevalence
rate of synchronous CRC in patients who have under-
gone colectomy within a few months of colonoscopy that
only showed LGD as the most advanced histologic ab-
normality. One recent meta-analysis revealed that the
positive predictive value for progression to HGD and/or
CRC from LGD is about 18%. However, significant vari-
ability in progression to HGD or CRC has been noted
between various studies. Some reveal a progression rate
of 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.
742 AGA
Thus, the decision to undergo colectomy versus contin-
ued surveillance in the setting of flat LGD should be indi-
vidualized and discussed at length among the patient, the
gastroenterologist, and the colorectal surgeon. For instance,
if flat LGD is detected in biopsy specimens on more than
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
should 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 indefinite, LGD, or HGD.
Is There Sufficient Rationale for
Performing Surveillance Colonoscopy
in 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 with
IBD at increased risk for developing CRC.
II. Patients with extensive UC or CD of the colon are most
likely to benefit from surveillance.
Proof that surveillance colonoscopy is effective in
patients with IBD requires demonstration of a reduction in
mortality due to CRC. Randomized controlled trials testing
surveillance colonoscopy have not been performed. In ad-
dition, randomized trials are not likely to be performed
because of ethical issues related to withholding surveillance
from a control group and the long duration of follow-up
needed to demonstrate a survival advantage. Nevertheless, a
large number of case series and 3 case-control studies have
suggested clinical benefit of surveillance colonoscopy for
patients with IBD. However, the Cochrane Group per-
formed a pooled analysis of published studies in patients
with UC and concluded that there is no clear evidence that
surveillance colonoscopy prolongs survival in patients with
extensive colitis. There was evidence that cancers tended to
be detected at an earlier stage in patients who had under-
gone surveillance, and had a better prognosis, compared to
patients who had not undergone surveillance. One impor-
tant limitation of the studies was the potential for lead-time
bias to contribute to the apparent benefit of surveillance
colonoscopy. 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 surveillance
colonoscopy offers a reasonable chance of detecting dyspla-
sia or early-stage CRC. Patients with ulcerative proctitis,
ulcerative proctosigmoiditis, or limited Crohn’s colitis do
GASTROENTEROLOGY Vol. 138, No. 2
not require surveillance colonoscopy but should follow age-
specific guidelines for CRC screening.
How Should Surveillance Colonoscopy
Be Performed?
I. The technique of surveillance colonoscopy in patients
with 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 1
to 3 years are suggested.
III. Careful inspection of the mucosa along with a sufficient
number of biopsy specimens should be obtained from all
anatomic segments of the colon.
To date, our understanding of the efficacy 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. Recommendations
regarding the preferred method of performing surveillance
colonoscopy are also based largely on the opinion of interna-
tional IBD experts. Surveillance colonoscopy is performed in a
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
all portions of the colon in patients with pancolitis. Because
dysplasia and cancer are more common in the left colon, it is
also recommended that more extensive sampling should be
performed in the left colon and particularly the rectum. Biopsy
specimens should also be obtained separately from areas of flat
mucosa surrounding the base of adenoma-like and non–ade-
noma-like DALMs. Equally important to obtaining a sufficient
number of biopsy specimens is careful visual inspection of the
colorectal mucosa during colonoscopy.
Chromoendoscopy, or other image-enhancing tech-
niques, are recommended for physicians with experience
with these techniques. With the use of enhanced endoscopic
techniques, targeted biopsies may be performed as an alter-
native to obtaining random biopsy specimens (see the next
section). Poor adherence of patients to their surveillance
program reduces the effectiveness of surveillance. The cur-
rently recommended guidelines regarding surveillance
colonoscopy are summarized as follows:
1. All patients, regardless of the extent of disease at initial
diagnosis, should undergo a screening colonoscopy a
maximum of 8 years after onset of symptoms, with
multiple biopsy specimens obtained throughout the en-
tire colon to assess the true microscopic extent of inflam-
mation.
2. Patients with ulcerative proctitis or ulcerative proctosig-
moiditis are not considered at increased risk for IBD-
February 2010
related CRC and thus may be managed on the basis of
average-risk recommendations.
3. Patients with extensive or left-sided colitis should begin
surveillance within 1 to 2 years after the initial screening
endoscopy.
4. The optimal surveillance interval has not been clearly
defined. After 2 negative examinations (no dysplasia or
cancer), further surveillance examinations should be per-
formed every 1 to 3 years. Recent data suggests that increas-
ing the frequency of surveillance colonoscopy to every 1 to
2 years after 20 years of disease is not needed for all patients
but should be individualized according to the presence or
absence of other risk factors (see the next section).
5. There are no prospective studies that have determined
the optimal number of biopsy specimens that should be
obtained to detect dysplasia reliably. Representative bi-
opsy specimens from each anatomic section of the colon
should be obtained. One study has recommended that a
minimum of 33 biopsy specimens be taken in patients
with 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 for
endoscopists who have expertise with this technique (see
the 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 performed
when the colonic disease is in remission.
9. Patients with a history of CRC in first-degree relatives,
ongoing active endoscopic or histologic inflammation,
or anatomic abnormalities such as a foreshortened colon,
stricture, or multiple inflammatory pseudopolyps may ben-
efit from more frequent surveillance examinations.
10. These recommendations also apply to patients with
Crohn’s colitis who have disease involving at least one
third of the length of the colon.
What Role Do the Newer Imaging
Techniques Play in Identifying and
Managing 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 detected
dysplasia is unknown.
III. Additional studies are needed to evaluate the efficiency of
other imaging methods, such as narrow band imaging
and confocal endomicroscopy, in detecting dysplasia.
Several imaging modalities, such as chromoendos-
copy with methylene blue or indigo carmine, narrow band
AGA 743
imaging, and confocal endomicroscopy, are currently being
studied as potential alternatives to white light endoscopy.
Several randomized studies suggest that chromoendoscopy
increases the yield of detecting dysplasia and may obviate
the need for multiple random biopsies. However, despite
improved detection methods of dysplastic lesions, in in-
stances where colectomy has been performed based on chro-
moendoscopy findings, unexpected cancers have not yet
been reported. The performance of chromoendoscopy is
subject to the skill of the endoscopist. In addition, high-
definition technology and enhanced magnification, is ren-
dering white light colonoscopy more accurate in detecting
dysplasia. Thus, at this time, normal white light colonos-
copy, using standard or high-definition colonoscopes along
with multiple colon biopsies, remains a reasonable method
of surveillance for patients with IBD. However, chromoen-
doscopy with targeted biopsies is considered an acceptable
alternative to white light endoscopy for endoscopists who
have experience with this technique. Training issues and the
time 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 Be
Used to Lower the Risk of Developing
Dysplasia or CRC in IBD?
Grade A: High certainty that the magnitude of net ben-
efits is substantial.
I. Ursodeoxycholic acid has demonstrated a significant reduction
in CRC in patients with UC who also have PSC.
Grade B: Moderate certainty that the magnitude of net
benefits is moderate.
I. Aminosalicylates are chemopreventive against CRC.
Grade D: High certainty that the magnitude of net
benefits is negative.
I. Oral or topical corticosteroids, while demonstrating antineo-
plastic effects in 2 studies, are associated with too many side
effects to warrant use as chemopreventive agents.
Grade Insufficient: No recommendation, insufficient
evidence to recommend for or against the use of thio-
purines, supplements, or statins.
I. Azathioprine or 6-mercaptopurine has not been consistently
associated with lower rates of CRC.
II. Folic acid supplements, calcium, multivitamins, or statins
have not been consistently associated with lower rates of CRC.
744 AGA
Chemopreventive agents that have been studied in
IBD 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 in
patients with IBD. Given the large number of patients
needed to perform these types of studies, they are not likely
to be performed in the near future. With the exception of 2
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
their conclusions from population-based registries or phar-
maceutical databases. Studies also vary as to whether the
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.
UDCA is commonly used in patients with UC who also
have PSC. Indeed, these patients are known to be among
those with the highest risk of CRC. There is strong
evidence that UDCA has a chemopreventive effect against
CRC. However, there is insufficient evidence to determine
whether 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 effect
of mesalamine for CRC (odds ratio, 0.51; 95% CI, 0.37– 0.69)
and for patients with dysplasia and CRC (odds ratio, 0.51;
95% CI, 0.38 – 0.69). The benefit occurred with either regular
use of mesalamine compounds or by use of at least 1.2
g/day of mesalamine equivalents. In this meta-analysis, use
of mesalamine was not significantly associated with a lower
risk of dysplasia (odds ratio, 1.18; 95% CI, 0.41–3.43), but
only 2 studies evaluated dysplasia as an end point. Most
studies have noted that sulfasalazine appears to have a less
protective effect compared with mesalamine.
Corticosteroid use has been analyzed in several studies,
most of which did not find 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
significant reduction of CRC risk. At this point, chronic
corticosteroid 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 drugs
represent the cornerstone of maintenance therapy, their use
in clinical practice is not in question. No study, except one,
has examined these agents as a primary variable in the
assessment of CRC risk in IBD. In the one study that
specifically evaluated the efficacy of immunomodulators in
reducing the risk of CRC, a protective effect of these agents
on the risk of progression to dysplasia or CRC was not
detected.
GASTROENTEROLOGY Vol. 138, No. 2
Four studies evaluated folate use in IBD, 2 of which
analyzed its use as a primary variable. These studies
suggested a trend toward protection against CRC in
folate users, but neither study demonstrated statistical
significance. No study has specifically analyzed a possible
chemopreventive role for calcium, multivitamins, or
statins. Thus there is insufficient evidence, either for or
against, the use of these agents for prevention of neopla-
sia in patients with IBD at this time.
Should Molecular Markers Be Applied
to Help Stratify Patients Into Low-Risk
and High-Risk Groups?
Grade Insufficient: No recommendation; insuffi-
cient evidence to recommend for or against the use
of 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 occur
in colitis-associated CRC. Much of the data regarding
types of molecular alterations in colitis-associated CRC
have 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 the
pathological spectrum of neoplasia (no dysplasia, indef-
inite for dysplasia, LGD, HGD, and CRC). In these stud-
ies, a genetic alteration that demonstrated preferential, or
increased, expression in neoplastic tissue was considered
a 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 or
CRC. 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. Several
studies suggest that aneuploidy occurs diffusely through-
out the colon and it usually (but not always) either
precedes, or develops synchronously with, dysplasia.
However, evaluation of aneuploidy by flow cytometry
requires considerable technical and professional exper-
tise, which limits its use in routine practice. At this time,
there is insufficient evidence to recommend for, or
against, the use of any other tissue, serum, or stool-based
biomarker in the evaluation of risk of dysplasia or CRC
in patients with IBD.
February 2010
FRANCIS A. FARRAYE
Section of Gastroenterology
Boston Medical Center
Boston University School of Medicine
Boston, Massachusetts
ROBERT D. ODZE
Department of Pathology
Brigham and Women’s Hospital
Harvard Medical School
Boston, Massachusetts
JAYNE EADEN
Department of Gastroenterology
University Hospital
Coventry, England
STEVEN H. ITZKOWITZ
The Dr Henry D. Janowitz Division of
Gastroenterology
Department of Medicine
Mount Sinai School of Medicine
New York, New York
AGA 745
In Collaboration With the AGA Institute Medical
Position Panel on Diagnosis and Management of
Colorectal Neoplasia in Inflammatory Bowel Disease
Reference
1. Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review
on the diagnosis and management of colorectal neoplasia in in-
flammatory bowel disease. Gastroenterology 2010;138:746 –
774.
Reprint requests
Address requests for reprints to: Chair, Clinical Practice and
Quality Management Committee, AGA National Office, 4930 Del Ray
Avenue, Bethesda, Maryland 20814. Phone: (301) 272-1189;
e-mail: SAgyeman@gastro.org.
Conflicts of interest
The authors disclose the following: Dr Farraye has received
research support from Prometheus Laboratories; is a consultant and
a member of the speaker’s bureau for Abbott, Centocor, Proctor &
Gamble, Prometheus Laboratories, Salix, and Shire; and is a
consultant for UCB. The remaining authors disclose no conflicts.