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Dysplasia in Inflammatory Bowel Disease: from Genetics to Treatment 37
tive and dysplastic epithelium is not always straight
forward. While the dysplastic epithelium shows cer-
tain histological changes that distinguish it from nor-
mal epithelium, it is not always easy to differentiate
dysplasia from the reactive type morphology seen in
cases of inflammation or repair. In a reactive process,
there are usually enlarged nuclei, nuclear pseudo-
stratification but no loss of polarity and no nuclear
coarse chromatin formation. They may both, howev-
er, show some degree of mucin loss together with
increased density of the cytoplasm and high mitotic
figures.
Macroscopically, dysplasia can be categorised as
either flat or raised. The former is usually detected
during random biopsies taken by conventional
colonoscopy [13]. In contrast, the raised dysplastic
areas are usually visible endoscopically and have
been referred to as a dysplasia associated lesion or
mass (DALM) [14]. Raised lesions can take many
forms including plaques, polyps, velvety patches,
clusters of polyps or nodular areas [13].
As mentioned earlier, the first problem encoun-
tered by the pathologist is the histologic recognition
of dysplasia, and its distinction from that of a repar-
ative process. As noted in several studies, there is a
significant degree of intra- and interobserver vari-
ability in recognising dysplasia, particularly in the
distinction between indefinite probably positive for
dysplasia vs. low-grade dysplasia [15, 16]. This neces-
sitates a well-accepted policy of diagnosing dysplasia
by two different pathologists with one of them having
a special interest in gastrointestinal pathology and
dysplasia [16]. The distinction between high-grade
dysplasia is less of an issue because the degree of con-
cordance is better than with low-grade dysplasia [17].
The distinction between high and low-grade dyspla-
sia bears significant consequences to the patient in
some colorectal surgical units because the detection
of high-grade dysplasia requires immediate interven-
tion, which is usually colectomy, since it is associated
with 40–70% of invasive carcinomas [18], while in
some centres, low-grade dysplasia requires a less rad-
ical approach.
In contrast to high-grade dysplasia, some studies
have shown that low-grade dysplastic change has a
positive predictive value of 7–24% for development
of cancer and 16–54% for progression to high-grade
dysplasia in 5 years, and this has been demonstrated
by the increase frequency of p53 mutation in low-
grade dysplasia [19, 20]. However, there are no strict
criteria for distinguishing between low and high-
grade dysplasia, and the distinction between them
depends on the subjective interpretation of the
reporting pathologist. An active chronic colitis that
shows marked reparative changes can be difficult if
not impossible to differentiate from genuine dyspla-
sia and, under such circumstances, a diagnosis of
indefinite for dysplasia is warranted.
Mapping studies by Levine et al. [21] and Rute-
gard et al. [22] have shown that dysplasia may be
localised to a small area within the colon, and may
require extensive sampling beyond what is clinically
or economically feasible, thus creating another hur-
dle in detecting the small foci of epithelial changes
that may require surgical intervention.
Sporadic Adenomas vs. Dysplasia Associated
Lesion/Mass (DALM)
Several different subtypes of DALMs in IBD have
been described. These subtypes broadly fall into two
forms, adenoma-like and non-adenoma like. This
distinction is based primarily on their gross/endo-
scopic appearance. Non-adenoma-like lesions are
usually large, sessile with a broad base, irregular
masses or ill-defined nodules. To some, a biopsy
finding of dysplasia in a non-adenoma-like DALM,
either low or high-grade, is usually an indication for
colectomy because of the high probability (between
30 to 80%) of an associated adenocarcinoma [14].
Adenoma-like DALM is present as an isolated, well-
circumscribed and pedunculated adenoma-like poly-
poid dysplastic lesion, which is basically not unlike
the appearance of a sporadic adenoma either endo-
scopically or macroscopically. In this instance, the
clinical differential diagnosis includes an adenoma-
like DALM in UC vs. a sporadic adenoma, a lesion
that occurs coincidentally in a patient with underly-
ing IBD.
The fact that sporadic adenomas can also arise
within colons affected by IBD creates a problem in
diagnosis and management. Sporadic adenoma aris-
ing in patients with IBD can sometimes be difficult if
not impossible to differentiate from IBD-associated
dysplasia (polypoid dysplasia). One can be confident
that one is dealing with a sporadic adenoma if it is
found in an area not affected by IBD (a right-sided
adenoma in a patient with left-sided colitis). On the
other hand, finding such a lesion in a colonic seg-
ment affected by IBD in a young age group is in
favour of polypoid dysplasia rather than adenomas,
as these tend to occur mostly in a middle age group
or older. However, if the adenoma-like dysplastic
lesion arises within an area involved by IBD, then this
problem becomes much more difficult. It used to be
recommended to ‘judge the lesion by the company of
the epithelium it keeps’. In other words, if the epithe-
lium adjacent to the lesion is dysplastic, then the
lesion is judged to be the same. We feel that is a fee-
ble way of addressing the issue scientifically.
In an attempt to distinguish sporadic adenomas
38 E. Salmo, P. O’Connolly, N. Haboubi
from adenoma-like dysplastic lesions arising in IBD,
studies have evaluated as to whether histologic fea-
tures [23], molecular genetic studies or the location
of the lesion can be used reliably to distinguish
between them. Torres et al. [24] evaluated 89 poly-
poid adenomatous lesions from 59 patients with IBD,
including 51 patients with UC and 8 patients with
CD, and correlated the morphologic features of these
adenoma-like lesions with clinical, endoscopic and
follow-up data. If the lesion was located proximal to
histologically diseased mucosa, lesions were classi-
fied as A, or probable sporadic adenomas. If they
developed within an area of colitis associated with
flat dysplasia or carcinoma, which was detected dur-
ing follow-up, lesions were classified as B, or proba-
ble IBD-associated polypoid dysplasia. If they were
located in an area of colitis, but with no flat dysplasia
or carcinoma on the follow-up evaluation, the lesions
were classified as C, or indeterminate type. In nine
patients with probable sporadic adenomas (group
A), follow-up information was available and none
developed subsequent dysplasia or adenocarcinoma.
In contrast, of the 31 patients with either indetermi-
nate polyps or probable IBD-associated dysplastic
lesions (groups B and C), in the follow-up informa-
tion, 13 patients either had or developed flat dysplas-
tic lesions or adenocarcinoma in adjacent mucosa
(including five patients with probable IBD-associated
dysplastic lesions who had flat dysplasia in adjacent
mucosa at the onset). Using these categories, it was
found that patients with probable IBD-associated
dysplastic lesions were younger (median age
48 years) than those with probable sporadic adeno-
mas (median age 63.5 years), were more likely to
have active colitis and were more likely to have a
longer duration of disease (median 11 vs. 5 years).
Histologically, patients with probable IBD-associated
dysplastic lesions more commonly had lamina pro-
pria mononuclear inflammation, lamina propria
neutrophilia and most importantly, were significant-
ly more likely to have an admixture of dysplastic and
non-dysplastic crypts on the surface of the polyp (60
vs. 16%). Others suggest that superficial, or the so-
called “top down”, dysplasia is more specific for a
subset of adenoma-like polyps. In such lesions, the
dysplastic glands are usually located in the upper
part of the polyp and confined to the surface, form-
ing a band like array [13].
Genetics of Dysplasia
Although several other studies have evaluated
immunohistochemical findings in these two groups
of lesions (DALM vs. sporadic adenoma), none have
been shown to be useful in this differential diagnosis
[25, 26]. However, some investigators have suggested
that IBD-associated adenoma-like DALMs has a
higher degree of p53, and a lower degree of nuclear
beta-catenin and bcl-2 staining in contrast to spo-
radic adenomas, thus p53 protein expression favours
DALM, and expression of bcl-2 and nuclear B-
catenin favours a sporadic adenoma (Table 4) [27,
28].
One study of UC-associated dysplasia and carci-
noma has shown that the tumour-suppressor gene
APC is demonstrated infrequently and plays an
unimportant role compared to sporadic colorectal
cancers. It has been shown that the APC gene was
mutated in more than 60% of sporadic adenomas
and CRC [29], while it was mutated in approximately
6% of colitic cancers [30].
Mutation in K-ras has been reported in cases of
ulcerative colitis with a villous and hypermucinous
mucosal surface prior to the appearance of dysplasia
and it was suggested that these particular cases
should be followed-up more frequently as a potential
risk lesion for cancer development [31]. However,
the majority of the studies revealed a lower incidence
of K-ras mutation in UC-associated cancer compared
to sporadic ones [32]. In a study by Odze et al.,there
were no significant differences in the frequencies of
loss of heterozygosity (LOH) of 3p, APC or p16 in the
UC-associated adenoma-like lesions that occurred
within areas of colitis compared to those that
occurred in a background of normal mucosa. These
data suggest that UC-associated flat dysplastic (non-
adenoma-like) DALMs have a different molecular
genotype than UC-associated adenoma-like lesions
as well as non-UC sporadic adenomas, although the
latter two lesions are pathogenetically similar, if not
identical, to one another [33, 34]. The tumour-sup-
pressor gene p53 is shown by many investigators to
be altered in UC-associated dysplasia and carcinoma.
Some use it to differentiate between reactive inflam-
matory epithelial changes and true dysplasia and
others use it as a tool to discriminate between DALM
and sporadic adenoma. Its positivity favours dyspla-
sia over reactive change and DALM over a sporadic
adenoma [35, 29].
Some authors reported clonal chromosomal alter-
ations in 85% of colitic cancers, 86% of UC-associat-
Table 4. Immunohistochemistry in DALM vs. sporadic ade-
noma
DALM Sporadic adenoma
P53 +-
Bcl-2 -+
B-catenin - +
Dysplasia in Inflammatory Bowel Disease: from Genetics to Treatment 39
ed dysplasia and 36% of non-neoplastic epithelium
[36]. The high rate of chromosomal alterations in
non-neoplastic epithelium in colitic cancer, com-
pared to the very low rate in sporadic cancers, has
lead to the suggestion that these changes appear early
in the neoplastic pathway of colitis.
Microsatellite instability was reported in cases of
high-grade dysplasia associated with IBD and also in
cases of colorectal cancer in a range between 46 to
50% in some studies and 3% in others. [37, 38].
Mutation of the p16
INK4a
promoter region (an
inhibitor of the cyclin-dependent protein kinase 4
and 6) was not demonstrated in cases of sporadic
colonic cancers. However, it has been shown to be
present in 70% of dysplastic lesion and 100% of col-
itic cancers in IBD patients [39]. Expression of apop-
tosis-related proteins like Fas and Bcl-xl (both with
negative or weak expression in sporadic tumours and
positive in UC-associated neoplasia) is sometimes
useful in distinguishing between IBD-dysplasia and
sporadic adenoma, thus leaving the patient with local
resection rather than colectomy [40].
Screening and Treatment Options of Patients with
Dysplasia-Associated IBD
The evidence of the association of dysplasia with
cancer in patients with IBD has been noticed since
the first publication of Crohn and Rosenberg early in
the 1900s [41–43]. The fact that dysplasia is com-
monly seen near areas of invasive carcinoma in up to
74% of resection specimens from IBD patients, has
lead to the conclusion that this is a precursor to the
invasive lesion [44]. The diagnosis of dysplasia in
patients with IBD is a crucial step because in some
centres it will leave the patient with either a colecto-
my or life-long surveillance to prevent the develop-
ment of cancer [25].
The rationale behind screening in these groups of
patients is based on the recognition that CRC in these
groups follows the sequence of chronic inflammation
with the subsequent development of dysplasia of the
colonic epithelium, progressing to carcinoma. This is
roughly the same argument used in detecting and
treating adenomatous polyps, since they are known
to be the classical precancerous lesions in the colon
and rectum. The issue when the diagnosis of dyspla-
sia is established is what to do or advise next. Classi-
cally, and according to the recommendations pro-
posed by Riddell et al., the procedure is to follow up
cases with low-grade dysplasia and operate on
DALMs and high-grade dysplasia. This seems at a
glance to be good simple advice; however, there have
been a few studies that have shown some data that
has made the decision more complex. Charles Bern-
stein says that “when low grade dysplasia is the pre-
operative diagnosis, cancer may already be present in
the colon in 20% of these cases”. He quoted the St
Marks series by saying that in about 50% of the cases
of CRC in UC, low-grade dysplasia is the only type of
dysplasia seen in the colonic resections adjacent or
away from the tumour. It is also important to know
that dysplasia may not be seen in 25% of patients
with CRC complicating IBD [45]. There is also
mounting evidence showing that the story of natural
progression from low-grade to high-grade dysplasia
and then to full-blown cancer can not always be sub-
stantiated. Dysplasia has been recognised as a pre-
malignant condition since the 1980s [46]. If dysplasia
is detected by random biopsy, its presence may cor-
relate with the presence of deposits of micro-invasive
adenocarcinoma. The presence of dysplasia in
colonic biopsies is a reliable histological marker
which can be used to predict which patients are at
risk of developing CRC before there is macroscopic
evidence of disease [47]. Prior to enrolling in surveil-
lance programmes, all patients should be counselled
as to the possibility of requiring a prophylactic proc-
tocolectomy with either a permanent end ileostomy
or formation of an ileo-anal pouch in order to pre-
vent the future development of CRC, if the presence
of dysplasia is confirmed. It is interesting to realise
that most of the rarely reported cases of carcinoma
arising in the ileo-anal pouch are those that have car-
cinoma or dysplasia in the initial resectates [18].
The British Society of Gastroenterology and the
Association of Coloproctology have suggested guide-
lines for the screening of asymptomatic colorectal
cancer in patients with inflammatory bowel disease.
These guidelines suggest that colonoscopy surveil-
lance with four random biopsies every 10 cm should
commence after the patient has endured the condi-
tion for a minimum of 8 years. The risk of CRC is rel-
atively low during the first decade of the disease. As a
result, the surveillance protocols recommend three
yearly colonoscopies for the first 12 years, then bi-
annual endoscopies for the next 10 years, followed
indefinitely with annual colonoscopy [48]. This is at
variance with the recommendation originally sug-
gested by Riddell et al. in their classic paper in 1983
(see Table 1) In high risk groups such as those
patients with positive family histories of CRC at a
young age or primary sclerosing cholangitis, annual
colonoscopy is recommended [49].
The overall sensitivity of direct colonoscopy for
the detection of dysplasia is between 70–85%. Biopsy
of any macroscopically visible lesion is advised along
with four random biopsies at 10-cm intervals. In
practice, the colonoscopy may be performed more
frequently, depending upon the severity of the illness
and the extent of colonic involvement.
40 E. Salmo, P. O’Connolly, N. Haboubi
Sampling error, where the endoscopist fails to take
an adequate number of biopsies to exclude dysplasia
or carcinoma [50], is also a known problem. The
detection of high-grade dysplasia (HGD) in flat
lesions is sufficient histological evidence for the rec-
ommendation for a prophylactic colectomy to be
made. Multifocal low-grade dysplasia (LGD) should
also be treated with a prophylactic proctocolectomy
[51, 52]. Until recently there has been no consensus
as to whether the detection of a single focus of low-
grade dysplasia could be managed by accelerated
colonoscopic surveillance prior to the detection of
HGD and the recommendation of proctocolectomy.
However, analysis of prospective studies assessing
continued colonoscopic screening after detection of
LGD has revealed that 53% of patients with LGD
developed CRC at 5 years. Twenty-four percent of
patients diagnosed with LGD after colonoscopy, who
had elected to be treated with proctocolectomy, had
unrecognised advanced CRC after histological analy-
sis of the colectomy specimen with a rate of progres-
sion to advanced neoplasia that approached 53%
[52]. In a separate study, the presence of dysplasia
was found to have a sensitivity of 81% and specificity
of 79% as a marker for the presence of a synchronous
CRC. The positive predictive value of the detection of
LGD was 70% [53]. In view of these results and other
similar studies, detection of LGD is now widely
accepted as an indication for prophylactic procto-
colectomy with formation of an ileo-anal pouch or
end ileostomy. However, many clinicians still pursue
a more conservative approach in treating LGD rather
than recommending surgery, since other studies
have presented a less worrisome prognosis of LGD.
Befrits et al. followed 60 patients with flat LGD and
found that none developed cancer on follow-up [54].
Any raised non-adenomatous mass containing
evidence of dysplasia on biopsy would also require a
proctocolectomy. Some suggest that dysplasia detect-
ed in adenomatous lesions can be safely treated with
endoscopic resection, preventing an unnecessary
colectomy. Unfortunately colonoscopy with random
biopsies of macroscopically normal looking mucosa
is an inherently unreliable technique due to the spo-
radic nature of dysplasia, which often leads to a low
detection rate of positive results [55]. Inaccuracies
may occur at different stages of the screening process
due to inadequate colonic biopsies: macroscopically
visible lesions which remain undetected after
colonoscopy due to operator technique. Errors that
lead to misinterpretation will lead to false positive or
negative biopsy results. One of the major criticisms
of CRC surveillance programmes is the failure of rou-
tine biopsy to detect the neoplasia that is subse-
quently found after histological analysis of colectomy
specimens after surgery for symptom control, in the
interval prior to the next surveillance colonoscopy.
The potential for areas of dysplasia to remain unde-
tected after colonoscopy may be a factor contributing
to the failure of screening to dramatically reduce the
incidence of CRC developing as a complication of
IBD. This limitation of colonoscopy needs to be dis-
cussed with patients willing to enter surveillance pro-
grammes, as the limited sensitivity of this test needs
to be evaluated by each individual against the poten-
tial complications that arise as a result of
colonoscopy. In UK practice, the development of an
iatrogenic colonic perforation or haemorrhage
requiring laparoscopy occurs in approximately 1:1
000 patients undergoing colonoscopy [56]. A full dis-
cussion of all of the possible advantages of surveil-
lance must be held with the patient prior to them
enrolling in the follow-up programme, in view of the
potential physical and psychological complications.
The most reliable method to date for predicting the
risk of CRC is the presence of confirmed dysplasia
from colonoscopic biopsies. However, as yet there
have been no randomised controlled trials to com-
pare the effectiveness of different surveillance pro-
grammes in improving survival from CRC in patients
with IBD. There are few actual studies which com-
pare outcomes of surveillance against no surveil-
lance. This is partly due to the recognition that dys-
plasia is a pre-malignant condition and early detec-
tion of neoplasia with subsequent prophylactic proc-
tocolectomy can reduce the number of deaths from
CRC. This is a powerful argument supporting the
implementation of surveillance programmes. The
opposing argument focuses on the finding that sur-
veillance has had little effect on reducing the mortal-
ity rate of IBD patients dying from CRC [57]. Histo-
logical analysis of specimens from prophylactic proc-
tocolectomies performed after the detection of dys-
plasia often reveals the presence of unexpected early
Dukes A or B cancers. Earlier detection may result in
reduced morbidity and improved survival for the
individual but this may be attributable to the lead
time bias of earlier diagnosis. There is no clear evi-
dence that screening has reduced the mortality rate
of patients with IBD [58]
. Attention has recently been
focused on developing an alternative approach to
improve the efficiency of surveillance programmes.
The routine practice of obtaining four random biop-
sies at 10-cm intervals generates a vast number of
biopsies for analysis, of which only a small propor-
tion contain evidence of dysplasia. This is an expen-
sive and highly laborious process with a low diagnos-
tic yield for both the endoscopist and pathologist.
There is great interest in developing new techniques
which can target areas of macroscopically invisible
dysplasia directly and obviate the need for random
biopsies. Chromoendoscopy is the term given to the
Dysplasia in Inflammatory Bowel Disease: from Genetics to Treatment 41
technique of endoscopically spraying the colonic
mucosa with dyes such as 0.1% methylene blue or
0.4% indigo carmine to emphasise unusual mucosal
irregularities [59]. This is an easily adapted proce-
dure which can be performed by the application of
dye to the colonic mucosa from a conventional
colonoscope. The rational behind chromoendoscopy
is based on the dyes not being absorbed by the
mucosa but simply pooling in the mucosal pits allow-
ing easier endoscopic identification of abnormal
mucosa [60]. In Vivo studies in animal subjects have
allowed analysis of patterns of dye uptake in colonic
mucosa which has been repeatedly verified by histo-
logical analysis of the resected or biopsied specimens
[61]. Clinical studies utilising chromoendoscopy
have indicated that this improved endoscopic tech-
nique provides better improved detection rates of
dysplastic lesions. The detection of flat lesions by
routine colonoscopy is very difficult as the mucosal
changes are very subtle. Intravital staining signifi-
cantly improves the endoscopic detection of flat
lesions [62]. These lesions are classified according to
the pit pattern system which was developed in
response to the enhanced images obtained from using
magnifying endoscopes. Two separate prospective tri-
als comparing the detection rates of neoplastic lesions
by traditional random biopsy on routine colonoscopy
followed by immediate repeat colonoscopy and tar-
geted biopsy after mucosal staining both testify that
detection of dysplasia is significantly improved by
chromoendoscopy [63, 64]. This finding has signifi-
cant implications for the screening of patients with
IBD, as the improved detection rates will result in
more patients undergoing prophylactic proctocolec-
tomies at an earlier stage, which may inevitably
include the detection of synchronous CRC at earlier
stages. Pan-colonic chromoendoscopy also detects a
large number of non-neoplastic lesions. To maximise
the detection of dysplasia and minimise the biopsy of
non-neoplastic tissue, the endoscopist must adhere to
targeting biopsies of lesions with suspicious staining
patterns as determined by the pit pattern system—
grade III and IV lesions are likely to represent neo-
plastic change. In a recent article on chromoen-
doscopy, it was suggested that the so-called SURFACE
guidelines in ulcerative colitis be followed [65].
1. Strict patient selection. Patients with histological-
ly proven ulcerative colitis and at least an 8-year
duration in clinical remission. Avoid patients with
active disease.
2. Unmask the mucosal surface. Excellent bowel
preparation is needed. Remove mucus and
remaining fluid in the colon when necessary.
3. Reduce peristaltic waves. When drawing back the
endoscope, a spasmolytic agent should be used (if
necessary).
4. Full length staining of the colon. Perform full length
staining of the colon (panchromoendoscopy) in
ulcerative colitis rather than local staining.
5. Augmented detection with dyes. Intravital stain-
ing with 0.4% indigo carmine or 0.1% methylene
blue should be used to unmask flat lesions more
frequently than with conventional colonoscopy.
6. Crypt architecture analysis. All lesions should be
analysed according to the pit pattern classifica-
tion. Whereas pit pattern types I–II suggests the
presence of non-malignant lesions, staining pat-
terns III–V suggest the presence of intraepithelial
neoplasias and carcinomas.
7. Endoscopic targeted biopsies. Perform targeted
biopsies of all mucosal alterations, particularly of
circumscript lesions with staining patterns indica-
tive of intraepithelial neoplasias and carcinomas
(pit patterns III–V).
The use of high resolution endoscopy and dye
staining is 97% sensitive and 93% specific in predict-
ing neoplasia [66]. Novel techniques that have been
developed include ultra high-powered magnifying
endoscopes which have 1 000 times greater magnifi-
cation and are able to visualise cellular microstruc-
tures. The resultant images of In Vivo cells have such
clarity that the possibility exists in the future of endo-
scopically generated virtual histology [69].
Other experimental techniques include Raman
spectroscopy, fluorescence spectroscopy light scat-
tering spectroscopy, optical coherence tomography
and confocal laser microscopy. However, at this time,
these techniques are still experimental [68]. It is pos-
sible that in the future these diagnostic techniques
will be used with molecular markers to improve
detection of neoplasia. The benefit of surveillance
techniques utilising chromoendoscopy for the detec-
tion of dysplasia in patients with long-term IBD are
enormous and as such are likely to initiate a radical
change in current practice during this decade. There
is wide support for offering patients with adenoma-
like polypoid dysplasia a local resection if certain cri-
teria are met. These include the absence of flat dys-
plasia in the multiple biopsies of the area adjacent to
the lesion or the absence of flat or raised dysplasia in
other parts of the colon, and the willingness of the
patient to undergo continued surveillance [13]. Laser
fluorescence spectroscopy for In Situ dysplasia diag-
nosis and faecal DNA testing are some of the tech-
niques that have been indicated as being useful in the
future [69]. A recent study had suggested that in
longstanding extensive ulcerative colitis, the severity
of colonic inflammation is an important determinant
of the risk of colorectal neoplasia. Endoscopic and
histological grading of inflammation could allow bet-
ter risk stratification for surveillance programmes
[70].
42 E. Salmo, P. O’Connolly, N. Haboubi
As we mentioned before, there seems to be no stan-
dard or universally agreed treatment for dysplasia. It
was Blackstone et al. who advocated in a case study
the importance of having a definitive radical surgery
(total colectomy) in cases of dysplasia and demon-
strated the horrid prognosis relating to the raised dys-
plastic lesions in patients with IBD [71]. Adenoma-
like lesions that occur proximal to histological areas
of colitis (i.e. right-sided lesion in a patient with left-
sided UC), can easily be diagnosed as a sporadic ade-
noma because it is well known that dysplasia related
to IBD develops only in areas involved by the inflam-
matory process. However, adenoma-like lesions that
occur within areas affected by colitis are more diffi-
cult to distinguish from true polypoid dysplastic
lesions related to the underlying colitis [24, 34].
Recent data, primarily based on the results of two fol-
low-up studies, suggest that IBD patients with an ade-
noma-like DALM, regardless of whether it has been
determined as representing a sporadic or an IBD-
related lesion, may be treated adequately by polypec-
tomy and continued surveillance if there is no evi-
dence of flat dysplasia elsewhere in the patient or
especially the base of the polyp [72–74]. Further stud-
ies may be needed to verify the above observations
but for the time being it seems that this has momen-
tarily alleviated the pressure on the pathologists to
differentiate between DALM and sporadic adenoma.
Conclusions
• Definition of dysplasia is standard.
• Classifications are clear.
• Genetic studies are variable and may be useful in
differentiating between lesions and helpful in
choosing treatment modalities.
• Treatment varies according to condition of lesion.
• Not all CRC in IBD follow the logic of the low-
grade dysplasia, high-grade dysplasia then carci-
noma sequence.
• Modified chromoendoscopy is more sensitive
than routine endoscopy in identifying dysplastic
epithelium.
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Introduction
Patients with inflammatory bowel disease (IBD) are
at an increased risk for colorectal cancer (CRC)
[1–4], but the quantisation of the risk of CRC in this
specific population varies widely in different studies.
However, CRC complicating ulcerative colitis (UC)
and Crohn’s disease (CD) only accounts for 1–2% of
all cases of CRC in the general population. Most cases
of CRC are either sporadic (65–85%) or familial
(10–30%; Fig. 1) [3–4].
CRC is considered a serious complication of the
disease and accounts for approximately 15% of all
deaths in IBD patients [5]. The mortality in patients
diagnosed with CRC who are also diagnosed with
IBD is higher than for sporadic CRC [6]. However,
much more is known about the risk in UC. The inci-
dence of colorectal cancer in patients with ulcerative
colitis is higher than in the general population. In a
meta-analysis, the overall prevalence of CRC in any
UC patient, based on 116 studies, was estimated to be
3.7%. The incidence rate corresponded to cumulative
probabilities of 2% by 10 years, 8% by 20 years and
18% by 30 years [7].
The major risk factors for the development of CRC
include young age at onset of IBD [1], extensive dis-
ease [8] and long disease duration [5]. It is biologi-
cally plausible that the excess cancer risk is second-
ary to chronic inflammation and it is recognised that
duration of colitis is an important risk factor for
CRC. Rutter et al. [9] showed for the first time that
increasing severity of colonic inflammation is associ-
ated with an increase in the rate of colorectal neopla-
sia in UC. Patients with disease extending to the
hepatic flexure or more proximally have the greatest
risk of CRC [10–12]. Most studies have found that the
risk of CRC increases after 15 to 20 years; approxi-
mately one decade later than in pancolitis in patients
with colitis confined to the left colon [8]. Patients
with ulcerative proctitis and proctosigmoiditis are
probably not at increased risk for CRC [13]. An
increased risk of CRC has been observed in patients
with UC complicated by primary sclerosing cholangi-
tis. In these cases, cancer was more likely to be in the
right colon, suggesting a possible role of bile acids in
oncogenesis [14].
The evidence for other potential risk factors is
scarce. Smoke [15], folate depletion [16–17] and a
positive family history of colon cancer [18
] may
affect the occurrence of CRC. A hypothesis has been
put forward according to which UC, CD and CRC
occur in predisposed patients because of a mixture of
genetic and environmental factors. One study has
shown that relatives of patients with both IBD and
CRC have an 80% increased risk of CRC [19]. In our
study, there is no statistically significant difference
between IBD and control cases of family members as
far as prevalence of malignant colorectal, digestive
extra-colonic or extra-digestive tract tumours [20].
Another recent study has investigated the prevalence
of all malignancies in first-degree relatives of CD
patients. The result showed a higher prevalence of
breast cancer in female relatives, mainly in mothers,
of CD patients compared with controls. The presence
of breast cancer was not associated with any specific
phenotype of the CD [21].
As in UC, Crohn’s disease of the colon carries an
increased risk of CRC. Ekbom et al. [1] found a rela-
tive risk of 5.6% for CRC among patients with CD,
whereas in another Swedish patient cohort study,
Persson et al. [22] did not find that the population
relative risk increased. Similarly, Fireman et al. [23]
from Israel and Jess et al. [24] in the Danish cohort,
did not find an increased risk of CRC among their
IBD: Cancer Risk and Surveillance
Gabriele Riegler, Ilaria Esposito
Fig. 1. Distribution of CRC
46 G. Riegler, I. Esposito
patients with CD. Although analyzing subgroups
within the CD study meant that there were few can-
cers identified, when patients with CD of >10-year
duration were analyzed, the relative risk for CRC was
4.8%. For those patients with at least 10 years of dis-
ease and no surgery within the first 10 years, the rel-
ative risk was 8.3%. Thus, even among this reported-
ly negative study, when variables such as disease
duration and possibly disease extent (based on no
surgery) are analysed, the relative risk increases [5].
In the study of Gillen et al. [25], however, it appears
that the malignant potential in CD and UC is of the
same order of magnitude. Cancer developed in
inflamed areas in both diseases, and was thus located
in the right colon in 49% of patients with CD com-
pared with 36% with UC, reflecting the difference in
inflammatory sites in the two cases. Adenocarcino-
mas develop only in affected segments of the small
intestine, and are difficult to diagnose at an early
stage because the radiological appearance is similar
to that of stricturing CD.
Pathogenesis of CRC in IBD
The pathogenesis of CRC in IBD is poorly under-
stood. However, several lines of evidence suggest that
the pathobiology is different than sporadic CRC:
1. the mean age of developing CRC in the setting of
IBD is lower than sporadic CRC (40–50 vs. 60
years).
2. Dysplasia in UC is preceded by a long history of
chronic inflammation and can be found at distant
sites from the cancer. In contrast, dysplasia in spo-
radic CRC is usually associated with a discrete
polyp without inflammation.
3. Mutations in the ras protooncogene are present in
40–60% of sporadic CRC and are probably an early
event; in contrast, these mutations are less fre-
quently observed in cancer associated with UC,
and are probably a late event [26–27].
4. Loss of heterozygosity for the p53 gene and src
activation occur earlier in cancers associated with
IBD than in sporadic CRC. Src activity in UC cor-
relates with the degree of dysplasia [28].
5. Abnormalities of the p53 locus are absent in non-
dysplastic mucosa of patients with sporadic CRC.
In contrast, non-dysplastic mucosa in UC fre-
quently has aneuploid DNA content and may
show clones of cells with loss of heterozygosity of
the p53 gene [29].
It is generally accepted that CRC in IBD is preced-
ed by dysplasia, which is defined as unequivocal neo-
plastic epithelium and is currently the most impor-
tant and best-defined marker of an increased risk of
malignancy. Dysplasia is present in >70% of UC
patients with carcinoma. Although it may occur in
any portion of the colon, it typically parallels the
location of cancer arising from chronically inflamed
mucosa [30–32]. From an endoscopic viewpoint, dys-
plasia is characterised as flat (endoscopically invisi-
ble but detected in mucosal specimens) or raised
(endoscopically visible), in which case “dysplasia
associated lesions or mass” (DALM) is applied, a
term that was coined by Blackstone et al. in 1981 [33].
In their study, 12 of 112 patients with long-standing
UC were found to have a DALM, and of these, seven
(58%) had carcinoma. Given the strong association
with cancer, the presence of DALM constituted a
strong indication for colectomy, which has become
the standard therapy for this type of lesion. DALM
are a heterogeneous population of tumours that may
endoscopically appear as a plaque, mass (irregular,
broad-based or strictured lesions), a discrete sessile
nodule, or polyp. The cancer risk is not equal among
these various subtypes. Unfortunately, most of the
previous studies of UC associated DALMs failed to
evaluate these lesions in relation to their gross
appearance. For instance, there is one specific sub-
type of discrete DALM that endoscopically and histo-
logically resembles a sporadic adenoma (isolated
dysplastic nodule or polyp) and, as such, poses a dif-
ficult diagnostic challenge both to clinicians and to
pathologists [34]. This is a critically important dis-
tinction, because an adenoma-like DALM is a
tumour that arises as a result of UC and, thus, is an
indication for colectomy, whereas an adenoma which
is also by definition a “polypoid dysplastic lesion”,
the development of which is unrelated to the under-
lying chronic colitis (but coincidentally exists with
it), is usually treated by polypectomy.
Since both UC and sporadic adenomas (SA) are
not uncommon disorders, it is not surprising that
gastroenterologists regularly encounter patients who
have both conditions. Sporadic adenomas coexist
with UC if they are located next (proximal) to the
colitis because UC-related dysplasia does not develop
from non-inflamed epithelium. UC associated ade-
noma-like DALMs were classified as lesions that were
located within histologically proven areas of colitis
and were associated with either synchronous or
metachronous flat dysplasia or adenocarcinoma [35].
A number of clinical, histologic and molecular fea-
tures have been studied to help make a distinction
between DALM and SA:
1. patients with non-adenoma-like DALM are more
likely to be younger and have a longer duration of
disease, more extensive disease, and larger lesions
[36].
2. Lesions that appear endoscopically as adenomas
(pedunculated or sessile) rather than having other
characteristics (such as flat, ulcerated, or plaque-
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