Introduction

The potential development of colorectal carcinoma(CRC) as a complication of either ulcerative colitis(UC) or Crohn’s disease (CD) is well recognised [1].Patients with UC have a lifetime risk, between 6–10times that of the general population of developingCRC, whereas patients with CD develop an increasedlife-time risk when more than 30% of the colon hasbecome involved [2]. The development of neoplasia,in the form of either colonic epithelial dysplasia oradenocarcinoma, appears to be related to factors suchas the severity and duration of the illness, the extentof colonic involvement and the overall responsivenessto medical intervention [3, 4]. Patients at higher riskare those with UC, extensive colitis, those with diseaseduration of more than 10 years, those with primarysclerosing cholangitis and patients with an early ageof onset of colitis [5, 6]. The risk of developing CRC asa result of longstanding CD is less than the risk facedby patients with UC in which, regardless of the extentof the colitis, the latter has been estimated as a 2% riskat 10 years, 8% at 20 years and 18% at 30 years [7]. Itis assumed that CRC in patients with inflammatorybowel disease (IBD) develops, in most instances, inthe background of colonic epithelial dysplasia.

This chapter looks briefly into the various defini-tions and classifications, pathological observations,genetic changes, types and validity of various surveil-lance programmes and treatment options of dyspla-sia complicating IBD.

Definition and Classification of Dysplasia inUlcerative Colitis

Dysplasia is defined as an unequivocal neoplasticchange that is intraepithelial and within confinementof the gland basement membrane or as an unequivo-cal neoplastic alteration of the colonic epithelium. Itmay be a marker of carcinoma or may itself be malig-nant and associated with invasion into the underly-ing tissue [8].

It is important to realise that, for a very importantand practical reason, diagnosing colonic dysplasia isone of the most challenging exercises that the surgi-cal pathologist can go through. This is because thediagnosis of dysplasia is subjective and unless thepathologist sticks to rigid criteria, the diagnosis canbe either missed or misdiagnosed. For that reason theDysplasia Morphology Study Group proposed abroad three-tiered classification scheme for the eval-uation of dysplasia. This was designed to alert thepathologist to the histopathological criteria and pit-falls of diagnosing dysplasia, and also to proposetreatment and surveillance strategies. The classifica-tion consisted of three main categories including (1)negative for dysplasia, (2) positive for dysplasia,either low-grade or high-grade and (3) indefinite fordysplasia (probably negative, unknown or probablypositive (Table 1) [8]. The importance of such classi-fications at that time was to advise a follow-up strat-egy, which is still used by some centres today. Whilstthis classification was met with general acceptancefrom practicing pathologists in Europe and NorthAmerica, it was soon discovered that our Japanesecolleagues have a lower threshold for using the termcancer in cases in which the tumour has not invadedthe muscularis mucosa and to which most Europeanand North American colleagues have given it theterm dysplasia. In other words the term cancer isused by one school of practice while the other school

Dysplasia in Inflammatory Bowel Disease: from Geneticsto Treatment

Emil Salmo, Patrick O’Connolly, Najib Haboubi

Table 1. Classification of dysplasia [8]

Category Recommended follow-up

Negative Regular 1 yearIndefinite

Probably negative Regular 1 yearUnknown Short intervalProbably positive Short interval

PositiveLow grade Short interval or colectomy if

there is a massHigh grade Colectomy

36 E. Salmo, P. O’Connolly, N. Haboubi

prefers the term dysplasia. In most centres in Europe,the term cancer, in regards to the colon, is given onlywhen there is invasion through the biological base-ment membrane of the colonic epithelium, i.e. themuscularis mucosa. Malignant tumours confined tothe mucosa have practically no metastatic potentialand therefore we prefer not to use such a term. In1993, the Research Committee on InflammatoryBowel Disease of the Ministry of Health and Welfareof Japan [9] proposed a variation of the classificationof Riddell et al. (Table 2); however, it was not univer-sally used. Riddell’s classification of dysplasiaremained unchanged until 2000 when a group of gas-trointestinal pathologists from Europe, Japan andNorth America gathered in Vienna to propose a newclassification to bridge the huge gap between the ter-minologies used by the various groups. The Viennaclassification categorises epithelial dysplasia, foundany where in the gastrointestinal tract including thecolon, as negative for dysplasia, indefinite for dyspla-sia, low- and high-grade mucosal neoplasia and sub-mucosal or deeper invasion by carcinoma (Table 3)[10]. Regarding this classification, high-grademucosal neoplasia encompassed the following cate-gories including dysplasia, non-invasive carcinomaand suspicious for invasive carcinoma. However,intramucosal carcinoma was included in category 5

(carcinoma) of the original Vienna classification butthen later was moved into category 4 (high-gradedysplasia) in the revised Vienna classification [11].Schlemper and Iwashita subsequently summarisedthe revised Vienna classification in a review article in2004 [12]. We feel that the original classification ofdysplasia by Riddell et al. has stood the test of timeand we recommend using it in conjunction with therevised Vienna classification [11, 12].

Morphological Features

According to Riddell et al. [8] dysplasia is strictly ahistopathological diagnosis and is characterisedmicroscopically by the following histological fea-tures:1. architectural changes often resembling colonic

adenoma.2. Cellular atypia as characterised by nuclear stratifi-

cation, loss of polarity, hyperchromasia and anincrease in mitotic figures. High-grade epithelialdysplasia commonly shows a greater degree ofglandular architectural abnormality (complexbudding and branching), with enlarged hyper-chromatic nuclei with prominent nucleoli andstratification (Fig. 1).

3. The above changes are sometimes associated withthe so-called ‘incomplete crypt maturation’. Thisis characterised by a marked reduction in thenumber of goblet cells (or their focal absence)rendering some of the crypts containing absorp-tive cells only and dystrophic goblet cells (upsidedown rotation of goblet cells/signet ring forma-tion).In practice, however, the distinction between reac-

Table 2. Histopathological classification of neoplasticepithelium in UC [9]

Category Description

UC-I InflammatoryUC-II IndefiniteUC-II a Probably inflammatoryUC-II b Probably neoplasticUC-III Neoplastic but non invasiveUC-IV Carcinoma

Research Committee on IBD of the Ministry of Health and Welfareof Japan

Table 3. Classification of gastrointestinal neoplasia (Viennaclassification) [10]

1. Negative for dysplasia/neoplasia2. Indefinite for dysplasia/neoplasia3. Non-invasive low-grade neoplasia (low-grade adeno-ma/dysplasia)4. Non-invasive high-grade neoplasia (high-grade adeno-ma/dysplasia, non-invasive carcinoma, suspicious forinvasion)5. Invasive neoplasia (intramucosal carcinoma, submu-cosal carcinoma or beyond)a

a In the modified Vienna classification [11, 12], intramucosal car-cinoma moved to category 4.

Fig. 1. Crypts showing high-grade dysplasia with nuclearstratification and pleomorphism together with numerousmitotic figures

Dysplasia in Inflammatory Bowel Disease: from Genetics to Treatment 37

tive and dysplastic epithelium is not always straightforward. While the dysplastic epithelium shows cer-tain histological changes that distinguish it from nor-mal epithelium, it is not always easy to differentiatedysplasia from the reactive type morphology seen incases of inflammation or repair. In a reactive process,there are usually enlarged nuclei, nuclear pseudo-stratification but no loss of polarity and no nuclearcoarse chromatin formation. They may both, howev-er, show some degree of mucin loss together withincreased density of the cytoplasm and high mitoticfigures.

Macroscopically, dysplasia can be categorised aseither flat or raised. The former is usually detectedduring random biopsies taken by conventionalcolonoscopy [13]. In contrast, the raised dysplasticareas are usually visible endoscopically and havebeen referred to as a dysplasia associated lesion ormass (DALM) [14]. Raised lesions can take manyforms 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 recognitionof dysplasia, and its distinction from that of a repar-ative process. As noted in several studies, there is asignificant degree of intra- and interobserver vari-ability in recognising dysplasia, particularly in thedistinction between indefinite probably positive fordysplasia vs. low-grade dysplasia [15, 16]. This neces-sitates a well-accepted policy of diagnosing dysplasiaby two different pathologists with one of them havinga special interest in gastrointestinal pathology anddysplasia [16]. The distinction between high-gradedysplasia 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 insome colorectal surgical units because the detectionof high-grade dysplasia requires immediate interven-tion, which is usually colectomy, since it is associatedwith 40–70% of invasive carcinomas [18], while insome centres, low-grade dysplasia requires a less rad-ical approach.

In contrast to high-grade dysplasia, some studieshave shown that low-grade dysplastic change has apositive predictive value of 7–24% for developmentof cancer and 16–54% for progression to high-gradedysplasia in 5 years, and this has been demonstratedby the increase frequency of p53 mutation in low-grade dysplasia [19, 20]. However, there are no strictcriteria for distinguishing between low and high-grade dysplasia, and the distinction between themdepends on the subjective interpretation of thereporting pathologist. An active chronic colitis thatshows marked reparative changes can be difficult ifnot impossible to differentiate from genuine dyspla-

sia and, under such circumstances, a diagnosis ofindefinite for dysplasia is warranted.

Mapping studies by Levine et al. [21] and Rute-gard et al. [22] have shown that dysplasia may belocalised to a small area within the colon, and mayrequire extensive sampling beyond what is clinicallyor economically feasible, thus creating another hur-dle in detecting the small foci of epithelial changesthat may require surgical intervention.

Sporadic Adenomas vs. Dysplasia AssociatedLesion/Mass (DALM)

Several different subtypes of DALMs in IBD havebeen described. These subtypes broadly fall into twoforms, adenoma-like and non-adenoma like. Thisdistinction is based primarily on their gross/endo-scopic appearance. Non-adenoma-like lesions areusually large, sessile with a broad base, irregularmasses or ill-defined nodules. To some, a biopsyfinding of dysplasia in a non-adenoma-like DALM,either low or high-grade, is usually an indication forcolectomy because of the high probability (between30 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 unlikethe appearance of a sporadic adenoma either endo-scopically or macroscopically. In this instance, theclinical differential diagnosis includes an adenoma-like DALM in UC vs. a sporadic adenoma, a lesionthat occurs coincidentally in a patient with underly-ing IBD.

The fact that sporadic adenomas can also arisewithin colons affected by IBD creates a problem indiagnosis and management. Sporadic adenoma aris-ing in patients with IBD can sometimes be difficult ifnot impossible to differentiate from IBD-associateddysplasia (polypoid dysplasia). One can be confidentthat one is dealing with a sporadic adenoma if it isfound in an area not affected by IBD (a right-sidedadenoma in a patient with left-sided colitis). On theother hand, finding such a lesion in a colonic seg-ment affected by IBD in a young age group is infavour of polypoid dysplasia rather than adenomas,as these tend to occur mostly in a middle age groupor older. However, if the adenoma-like dysplasticlesion arises within an area involved by IBD, then thisproblem becomes much more difficult. It used to berecommended to ‘judge the lesion by the company ofthe epithelium it keeps’. In other words, if the epithe-lium adjacent to the lesion is dysplastic, then thelesion 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 locationof the lesion can be used reliably to distinguishbetween them. Torres et al. [24] evaluated 89 poly-poid adenomatous lesions from 59 patients with IBD,including 51 patients with UC and 8 patients withCD, and correlated the morphologic features of theseadenoma-like lesions with clinical, endoscopic andfollow-up data. If the lesion was located proximal tohistologically diseased mucosa, lesions were classi-fied as A, or probable sporadic adenomas. If theydeveloped within an area of colitis associated withflat dysplasia or carcinoma, which was detected dur-ing follow-up, lesions were classified as B, or proba-ble IBD-associated polypoid dysplasia. If they werelocated in an area of colitis, but with no flat dysplasiaor carcinoma on the follow-up evaluation, the lesionswere classified as C, or indeterminate type. In ninepatients with probable sporadic adenomas (groupA), follow-up information was available and nonedeveloped subsequent dysplasia or adenocarcinoma.In contrast, of the 31 patients with either indetermi-nate polyps or probable IBD-associated dysplasticlesions (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-associateddysplastic lesions who had flat dysplasia in adjacentmucosa at the onset). Using these categories, it wasfound that patients with probable IBD-associateddysplastic lesions were younger (median age48 years) than those with probable sporadic adeno-mas (median age 63.5 years), were more likely tohave active colitis and were more likely to have alonger duration of disease (median 11 vs. 5 years).Histologically, patients with probable IBD-associateddysplastic lesions more commonly had lamina pro-pria mononuclear inflammation, lamina proprianeutrophilia and most importantly, were significant-ly more likely to have an admixture of dysplastic andnon-dysplastic crypts on the surface of the polyp (60vs. 16%). Others suggest that superficial, or the so-called “top down”, dysplasia is more specific for asubset of adenoma-like polyps. In such lesions, thedysplastic glands are usually located in the upperpart of the polyp and confined to the surface, form-ing a band like array [13].

Genetics of Dysplasia

Although several other studies have evaluatedimmunohistochemical findings in these two groupsof lesions (DALM vs. sporadic adenoma), none havebeen shown to be useful in this differential diagnosis

[25, 26]. However, some investigators have suggestedthat IBD-associated adenoma-like DALMs has ahigher degree of p53, and a lower degree of nuclearbeta-catenin and bcl-2 staining in contrast to spo-radic adenomas, thus p53 protein expression favoursDALM, 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 geneAPC is demonstrated infrequently and plays anunimportant role compared to sporadic colorectalcancers. It has been shown that the APC gene wasmutated in more than 60% of sporadic adenomasand CRC [29], while it was mutated in approximately6% of colitic cancers [30].

Mutation in K-ras has been reported in cases ofulcerative colitis with a villous and hypermucinousmucosal surface prior to the appearance of dysplasiaand it was suggested that these particular casesshould be followed-up more frequently as a potentialrisk lesion for cancer development [31]. However,the majority of the studies revealed a lower incidenceof K-ras mutation in UC-associated cancer comparedto sporadic ones [32]. In a study by Odze et al., therewere no significant differences in the frequencies ofloss of heterozygosity (LOH) of 3p, APC or p16 in theUC-associated adenoma-like lesions that occurredwithin areas of colitis compared to those thatoccurred in a background of normal mucosa. Thesedata suggest that UC-associated flat dysplastic (non-adenoma-like) DALMs have a different moleculargenotype than UC-associated adenoma-like lesionsas well as non-UC sporadic adenomas, although thelatter two lesions are pathogenetically similar, if notidentical, to one another [33, 34]. The tumour-sup-pressor gene p53 is shown by many investigators tobe altered in UC-associated dysplasia and carcinoma.Some use it to differentiate between reactive inflam-matory epithelial changes and true dysplasia andothers use it as a tool to discriminate between DALMand sporadic adenoma. Its positivity favours dyspla-sia over reactive change and DALM over a sporadicadenoma [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 innon-neoplastic epithelium in colitic cancer, com-pared to the very low rate in sporadic cancers, haslead to the suggestion that these changes appear earlyin the neoplastic pathway of colitis.

Microsatellite instability was reported in cases ofhigh-grade dysplasia associated with IBD and also incases of colorectal cancer in a range between 46 to50% in some studies and 3% in others. [37, 38].Mutation of the p16INK4a promoter region (aninhibitor of the cyclin-dependent protein kinase 4and 6) was not demonstrated in cases of sporadiccolonic cancers. However, it has been shown to bepresent 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 withnegative or weak expression in sporadic tumours andpositive in UC-associated neoplasia) is sometimesuseful in distinguishing between IBD-dysplasia andsporadic adenoma, thus leaving the patient with localresection rather than colectomy [40].

Screening and Treatment Options of Patients withDysplasia-Associated IBD

The evidence of the association of dysplasia withcancer in patients with IBD has been noticed sincethe first publication of Crohn and Rosenberg early inthe 1900s [41–43]. The fact that dysplasia is com-monly seen near areas of invasive carcinoma in up to74% of resection specimens from IBD patients, haslead to the conclusion that this is a precursor to theinvasive lesion [44]. The diagnosis of dysplasia inpatients with IBD is a crucial step because in somecentres 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 ofpatients is based on the recognition that CRC in thesegroups follows the sequence of chronic inflammationwith the subsequent development of dysplasia of thecolonic epithelium, progressing to carcinoma. This isroughly the same argument used in detecting andtreating adenomatous polyps, since they are knownto be the classical precancerous lesions in the colonand 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 upcases with low-grade dysplasia and operate onDALMs and high-grade dysplasia. This seems at aglance to be good simple advice; however, there havebeen a few studies that have shown some data thathas made the decision more complex. Charles Bern-

stein says that “when low grade dysplasia is the pre-operative diagnosis, cancer may already be present inthe colon in 20% of these cases”. He quoted the StMarks series by saying that in about 50% of the casesof CRC in UC, low-grade dysplasia is the only type ofdysplasia seen in the colonic resections adjacent oraway from the tumour. It is also important to knowthat dysplasia may not be seen in 25% of patientswith CRC complicating IBD [45]. There is alsomounting evidence showing that the story of naturalprogression from low-grade to high-grade dysplasiaand 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 dysplasiais detected by random biopsy, its presence may cor-relate with the presence of deposits of micro-invasiveadenocarcinoma. The presence of dysplasia incolonic biopsies is a reliable histological markerwhich can be used to predict which patients are atrisk of developing CRC before there is macroscopicevidence of disease [47]. Prior to enrolling in surveil-lance programmes, all patients should be counselledas to the possibility of requiring a prophylactic proc-tocolectomy with either a permanent end ileostomyor formation of an ileo-anal pouch in order to pre-vent the future development of CRC, if the presenceof dysplasia is confirmed. It is interesting to realisethat most of the rarely reported cases of carcinomaarising in the ileo-anal pouch are those that have car-cinoma or dysplasia in the initial resectates [18].

The British Society of Gastroenterology and theAssociation of Coloproctology have suggested guide-lines for the screening of asymptomatic colorectalcancer in patients with inflammatory bowel disease.These guidelines suggest that colonoscopy surveil-lance with four random biopsies every 10 cm shouldcommence 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 aresult, the surveillance protocols recommend threeyearly colonoscopies for the first 12 years, then bi-annual endoscopies for the next 10 years, followedindefinitely with annual colonoscopy [48]. This is atvariance 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 thosepatients with positive family histories of CRC at ayoung age or primary sclerosing cholangitis, annualcolonoscopy is recommended [49].

The overall sensitivity of direct colonoscopy forthe detection of dysplasia is between 70–85%. Biopsyof any macroscopically visible lesion is advised alongwith four random biopsies at 10-cm intervals. Inpractice, the colonoscopy may be performed morefrequently, depending upon the severity of the illnessand the extent of colonic involvement.

40 E. Salmo, P. O’Connolly, N. Haboubi

Sampling error, where the endoscopist fails to takean adequate number of biopsies to exclude dysplasiaor carcinoma [50], is also a known problem. Thedetection of high-grade dysplasia (HGD) in flatlesions is sufficient histological evidence for the rec-ommendation for a prophylactic colectomy to bemade. Multifocal low-grade dysplasia (LGD) shouldalso be treated with a prophylactic proctocolectomy[51, 52]. Until recently there has been no consensusas to whether the detection of a single focus of low-grade dysplasia could be managed by acceleratedcolonoscopic surveillance prior to the detection ofHGD and the recommendation of proctocolectomy.However, analysis of prospective studies assessingcontinued colonoscopic screening after detection ofLGD has revealed that 53% of patients with LGDdeveloped CRC at 5 years. Twenty-four percent ofpatients diagnosed with LGD after colonoscopy, whohad elected to be treated with proctocolectomy, hadunrecognised 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 dysplasiawas found to have a sensitivity of 81% and specificityof 79% as a marker for the presence of a synchronousCRC. The positive predictive value of the detection ofLGD was 70% [53]. In view of these results and othersimilar studies, detection of LGD is now widelyaccepted as an indication for prophylactic procto-colectomy with formation of an ileo-anal pouch orend ileostomy. However, many clinicians still pursuea more conservative approach in treating LGD ratherthan recommending surgery, since other studieshave presented a less worrisome prognosis of LGD.Befrits et al. followed 60 patients with flat LGD andfound that none developed cancer on follow-up [54].

Any raised non-adenomatous mass containingevidence of dysplasia on biopsy would also require aproctocolectomy. Some suggest that dysplasia detect-ed in adenomatous lesions can be safely treated withendoscopic resection, preventing an unnecessarycolectomy. Unfortunately colonoscopy with randombiopsies of macroscopically normal looking mucosais an inherently unreliable technique due to the spo-radic nature of dysplasia, which often leads to a lowdetection rate of positive results [55]. Inaccuraciesmay occur at different stages of the screening processdue to inadequate colonic biopsies: macroscopicallyvisible lesions which remain undetected aftercolonoscopy due to operator technique. Errors thatlead to misinterpretation will lead to false positive ornegative biopsy results. One of the major criticismsof CRC surveillance programmes is the failure of rou-tine biopsy to detect the neoplasia that is subse-quently found after histological analysis of colectomyspecimens 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 contributingto the failure of screening to dramatically reduce theincidence of CRC developing as a complication ofIBD. This limitation of colonoscopy needs to be dis-cussed with patients willing to enter surveillance pro-grammes, as the limited sensitivity of this test needsto be evaluated by each individual against the poten-tial complications that arise as a result ofcolonoscopy. In UK practice, the development of aniatrogenic colonic perforation or haemorrhagerequiring laparoscopy occurs in approximately 1:1000 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 themenrolling in the follow-up programme, in view of thepotential physical and psychological complications.The most reliable method to date for predicting therisk of CRC is the presence of confirmed dysplasiafrom colonoscopic biopsies. However, as yet therehave been no randomised controlled trials to com-pare the effectiveness of different surveillance pro-grammes in improving survival from CRC in patientswith 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 fromCRC. This is a powerful argument supporting theimplementation of surveillance programmes. Theopposing 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 earlyDukes A or B cancers. Earlier detection may result inreduced morbidity and improved survival for theindividual but this may be attributable to the leadtime bias of earlier diagnosis. There is no clear evi-dence that screening has reduced the mortality rateof patients with IBD [58]. Attention has recently beenfocused on developing an alternative approach toimprove the efficiency of surveillance programmes.The routine practice of obtaining four random biop-sies at 10-cm intervals generates a vast number ofbiopsies 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 techniqueswhich can target areas of macroscopically invisibledysplasia directly and obviate the need for randombiopsies. Chromoendoscopy is the term given to the

Dysplasia in Inflammatory Bowel Disease: from Genetics to Treatment 41

technique of endoscopically spraying the colonicmucosa with dyes such as 0.1% methylene blue or0.4% indigo carmine to emphasise unusual mucosalirregularities [59]. This is an easily adapted proce-dure which can be performed by the application ofdye to the colonic mucosa from a conventionalcolonoscope. The rational behind chromoendoscopyis based on the dyes not being absorbed by themucosa but simply pooling in the mucosal pits allow-ing easier endoscopic identification of abnormalmucosa [60]. In Vivo studies in animal subjects haveallowed analysis of patterns of dye uptake in colonicmucosa which has been repeatedly verified by histo-logical analysis of the resected or biopsied specimens[61]. Clinical studies utilising chromoendoscopyhave indicated that this improved endoscopic tech-nique provides better improved detection rates ofdysplastic lesions. The detection of flat lesions byroutine colonoscopy is very difficult as the mucosalchanges are very subtle. Intravital staining signifi-cantly improves the endoscopic detection of flatlesions [62]. These lesions are classified according tothe pit pattern system which was developed inresponse to the enhanced images obtained from usingmagnifying endoscopes. Two separate prospective tri-als comparing the detection rates of neoplastic lesionsby traditional random biopsy on routine colonoscopyfollowed by immediate repeat colonoscopy and tar-geted biopsy after mucosal staining both testify thatdetection of dysplasia is significantly improved bychromoendoscopy [63, 64]. This finding has signifi-cant implications for the screening of patients withIBD, as the improved detection rates will result inmore patients undergoing prophylactic proctocolec-tomies at an earlier stage, which may inevitablyinclude the detection of synchronous CRC at earlierstages. Pan-colonic chromoendoscopy also detects alarge number of non-neoplastic lesions. To maximisethe detection of dysplasia and minimise the biopsy ofnon-neoplastic tissue, the endoscopist must adhere totargeting biopsies of lesions with suspicious stainingpatterns 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 SURFACEguidelines in ulcerative colitis be followed [65].1. Strict patient selection. Patients with histological-

ly proven ulcerative colitis and at least an 8-yearduration in clinical remission. Avoid patients withactive disease.

2. Unmask the mucosal surface. Excellent bowelpreparation is needed. Remove mucus andremaining fluid in the colon when necessary.

3. Reduce peristaltic waves. When drawing back theendoscope, a spasmolytic agent should be used (ifnecessary).

4. Full length staining of the colon. Perform full lengthstaining of the colon (panchromoendoscopy) inulcerative colitis rather than local staining.

5. Augmented detection with dyes. Intravital stain-ing with 0.4% indigo carmine or 0.1% methyleneblue should be used to unmask flat lesions morefrequently than with conventional colonoscopy.

6. Crypt architecture analysis. All lesions should beanalysed according to the pit pattern classifica-tion. Whereas pit pattern types I–II suggests thepresence of non-malignant lesions, staining pat-terns III–V suggest the presence of intraepithelialneoplasias and carcinomas.

7. Endoscopic targeted biopsies. Perform targetedbiopsies of all mucosal alterations, particularly ofcircumscript 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 beendeveloped include ultra high-powered magnifyingendoscopes which have 1 000 times greater magnifi-cation and are able to visualise cellular microstruc-tures. The resultant images of In Vivo cells have suchclarity that the possibility exists in the future of endo-scopically generated virtual histology [69].

Other experimental techniques include Ramanspectroscopy, fluorescence spectroscopy light scat-tering spectroscopy, optical coherence tomographyand confocal laser microscopy. However, at this time,these techniques are still experimental [68]. It is pos-sible that in the future these diagnostic techniqueswill be used with molecular markers to improvedetection of neoplasia. The benefit of surveillancetechniques utilising chromoendoscopy for the detec-tion of dysplasia in patients with long-term IBD areenormous and as such are likely to initiate a radicalchange in current practice during this decade. Thereis 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 tothe lesion or the absence of flat or raised dysplasia inother parts of the colon, and the willingness of thepatient to undergo continued surveillance [13]. Laserfluorescence 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 thefuture [69]. A recent study had suggested that inlongstanding extensive ulcerative colitis, the severityof colonic inflammation is an important determinantof the risk of colorectal neoplasia. Endoscopic andhistological 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. Itwas Blackstone et al. who advocated in a case studythe 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 areasof 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 relatedto IBD develops only in areas involved by the inflam-matory process. However, adenoma-like lesions thatoccur within areas affected by colitis are more diffi-cult to distinguish from true polypoid dysplasticlesions 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 beendetermined 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 orespecially the base of the polyp [72–74]. Further stud-ies may be needed to verify the above observationsbut for the time being it seems that this has momen-tarily alleviated the pressure on the pathologists todifferentiate 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 inchoosing 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 sensitivethan routine endoscopy in identifying dysplasticepithelium.

References

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