75 25 dysplasia in inflammatory 25 bowel diseases...

Dysplasia in inflammatorybowel diseases: Definition

and clinical impactKarel Geboes PhD MD1, Paul Rutgeerts PhD MD2

The increased risk of malignancy, more specifically of co-lorectal cancer (CRC), is a major problem in the long

term management of patients with chronic inflammatory

bowel diseases (IBD). The risk of CRC in longstanding ul-cerative colitis (UC) has been particularly in focus since therecognition of this complication in 1928, and management

Can J Gastroenterol Vol 13 No 8 October 1999 671

This mini-review was prepared from a presentation made at the World Congress of Gastroenterology, September 6 to 11, 1998, Vienna, Austria1GI Pathology Unit, 2Department of Gastroenterology, University Hospital, KU Leuven, BelgiumCorrespondence and reprints: Karel Geboes, Department of Pathology, University Hospital KU Leuven, Minderbroedersstraat 12, 3000 Leuven,

Belgium, Telephone 32-16-33-65-84, fax 32-16-33-65-48, e-mail [email protected] for publication December 1, 1998. Accepted December 10, 1998

MINI-REVIEW

K Geboes, P Rutgeerts. Dysplasia in inflammatory bowel dis-ease: Definition and clinical impact. Can J Gastroenterol1999;13(8):671-678. Dysplasia is a morphological term thatethymologically means ‘malformation’. For the definition of in-flammatory bowel disease-related dysplasia, the nature and originof the malformation are stressed and the lesion is defined as anepithelial malformation that is unequivocally neoplastic but non-invasive. The use of a precise definition is necessary because of theclinical consequences related to the finding of dysplasia in IBD.The microscopic diagnosis of dysplasia, however, remains diffi-cult. Clinically, it is important to make a proper differential diag-nosis between polypoid IBD-related dysplasia and sporadicadenoma occurring in IBD, and between therapy-related ‘pseud-odysplasia’ and genuine dysplasia. When dysplasia is diagnosed, asecond opinion may be indicated because of the clinical conse-quences. Additional techniques to search for genetic defects asso-ciated with carcinogenesis can help to support the diagnosis. Theycan identify changes in DNA content and molecular changes re-sulting from defects of genes controlling cell proliferation anddeath or tissue structure. These changes can, however, be absent,appear early or late in the transition from normality toward dyspla-sia and cancer, or appear during repair. Positive findings indicatean increased cancer risk, but the magnitude of the risk remains tobe defined. A positive diagnosis of genuine dysplasia necessitatesclinical action – either follow-up of the patient or treatment. Inpractice, treatment means surgery because dysplasia can be a pre-cursor and/or a marker of malignancy, except for sporadic adeno-mas, which can be removed locally.

Key Words: Dysplasia; Inflammatory bowel disease

La dysplasie dans les maladies inflammatoiresde l’intestin : définition et impact cliniqueRÉSUMÉ : Le terme dysplasie est un terme morphologique qui étymolo-giquement signifie « malformation ». Pour ce qui est de la définition de ladysplasie liée aux maladies inflammatoires de l’intestin (MII), on insistesur la nature et l’origine de la malformation et la lésion est définie commeune malformation épithéliale qui est, sans équivoque, néoplasique maisnon invasive. L’emploi d’une définition précise est nécessaire à cause desconséquences cliniques liées à la découverte d’une dysplasie dans une MII.Cependant, le diagnostic microscopique d’une dysplasie reste difficile.Cliniquement, il est important de poser un diagnostic différentiel correctentre la dysplasie de polypes liée à une MII et un adénome sporadiquesurvenant dans la MII, et entre la « pseudodysplasie » liée à un traitementet la dysplasie authentique. Le diagnostic d’une dysplasie nécessite lademande d’un deuxième avis à cause des conséquences cliniques. Destechniques additionnelles de dépistage de défauts génétiques associés à unecarcinogenèse peuvent permettre d’étayer le diagnostic. Ces techniquespeuvent identifier des changements dans le contenu de l’ADN et deschangements moléculaires résultant de défauts de gènes contrôlant laprolifération et la mort cellulaires ou la structure des tissus. Toutefois, ceschangements peuvent être absents, apparaître tôt ou tardivement dans laphase de transition qui va de la normalité vers la dysplasie et le cancer, ousurvenir pendant la réparation. Les données positives révèlent un risque decancer accru, mais l’ampleur du risque reste à être déterminée. Undiagnostic positif de dysplasie authentique nécessite une action clinique –soit le suivi du patient ou un traitement. En pratique, traiter signifie opérerpuisque la dysplasie peut être un précurseur ou un marqueur de malignité,sauf dans le cas d’adénomes sporadiques qui peuvent être enlevés par voielocale.

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strategies have been controversial ever since (1). Premalig-nant polypoid changes of the mucosa associated with CRCin UC were recognized in the late 1950s and later describedin more detail in flat mucosa as precancerous changes (2,3).

These alterations were later referred to as dysplasia. Look-ing for dysplasia in endoscopic biopsies has, since then, beenused for secondary prevention and in surveillance programsfor the early detection of CRC in IBD. However, the practi-cal application and the cost effectiveness of this search arenot entirely satisfactory because of problems with inter- andintraobserver variability among pathologists and because ofuncertainties in the clinical interpretation of the report re-sulting from the histopathological assessment of dysplasia.The purpose of the present review is to clarify the definitionof dysplasia and to discuss its relation with the molecular ge-netics associated with carcinogenesis.

DEFINITION OF DYSPLASIA‘Dysplasia’ is a word derived from the ancient Greek lan-guage. It is composed of two elements – ‘dys’ and ‘plasis’.‘Dys’ means ‘bad’ or ‘wrong’ – as in dysphagia, to eat badly, orin dyspepsia, to digest badly. ‘Plasis’ means ‘form’, as in plas-tic arts. The original meaning of dysplasia is thus malforma-tion, or a morphologic structure that is different from what isnormally expected. ‘Dysplasia’ is a term that is commonlyused in medicine for various and highly different macro-scopic and microscopic lesions, occurring in various organsystems. Fibromuscular arterial dysplasia and dysplasia of thekidney are two examples of the widespread use of this term.The term ‘fibromuscular arterial dysplasia’, as used in thecirculatory system, is an arterial disease, most often occuringin the renal arteries as a reversible cause of renal hyperten-sion and characterized by accumulation of cellular fibroustissue in the intima (the inner layer of the arteries) obstruct-ing the lumen and inducing ischemia. Dysplasia of the kid-ney is a congenital condition resulting from a disturbeddifferentiation of nephrogenic tissue and characterized bythe persistence of tissues that are normally only found in theembryo. The use of ‘dysplasia’ as a terminology for such dif-ferent lesions is understandable because of its original signifi-cance.

When used as such, however, the origin and meaning ofthe term dysplasia are undefined. The origin of a malforma-tion can indeed be variable. It can be congenital (hereditaryor not) or acquired. If acquired, the dysplastic transforma-tion can be regenerative (due to healing and repair followingdamage) or neoplastic (degenerative). Although the word‘dysplasia’ is sometimes used to describe macroscopic lesions,its main use is in histopathology. In general pathology, it isused to describe both epithelial and stromal lesions. It canstill mean ‘only malformation’ or it can be related to neopla-sia and malignancy. This double meaning exists also in gas-trointestinal pathology, where dysplasia in angiodysplasia, amisnomer for vascular ectasia, or in neuronal dysplasia de-scribes a malformation, either acquired or congenital (4). Inboth these conditions, dysplasia is used for stromal lesions.When used for alterations of the epithelium lining the gas-

trointestinal tract, the meaning of dysplasia is usually en-tirely different, and it is understood that there is a relationwith neoplasia. Yet there are numerous definitions available,even for epithelial lesions of the gastrointestinal tract, andthe relation with neoplasia may be either strong or weak.

Dysplasia has been defined as a lesion in which part of theepithelium is replaced by cells showing varying degrees ofatypia, or as atypia. The latter definition is, however, usuallyrestricted to the description of cytological abnormalities,while the word ‘dysplasia’ also encompasses changes in ar-chitecture and aberrant differentiation in addition to possi-ble cytological disturbances. The classical and most usualmanifestation of gastrointestinal dysplasia, according to thisdefinition, corresponds to a circumscribed, elevated lesion oradenoma (5).

In some textbooks, tissue is considered dysplastic when“the cellular architecture is distorted or deficient” (6).Changes in tissular architecture and the appearance of im-mature cells (altered differentiation) are, however, phenom-ena that also occur during repair. Restitution, one of thehealing mechanisms occurring in the gastrointestinal tract,is characterized by increased migration of young, immatureepithelial cells, covering up superficial defects (7).

The application of a purely morphological definition ofdysplasia is, therefore, not always adapted to the possibleclinical consequences. In earlier studies of early gastric can-cer, dysplasia was also defined as a process of disordered cellgrowth, as epithelial atypia or alteration, or as excessive ab-normal proliferation of the gastric epithelium, microscopi-cally recognized on the basis of cellular atypia, abnormalmaturation and a disorganized mucosal architecture. The le-sions were subdivided into several categories. Usually a dis-tinction was made between different grades. A variety ofexperimental investigations and follow-up studies of patientsshowed that mild degrees of dysplasia, as used in some ofthese classifications, were clinically irrelevant and largely re-active in nature (8-10).

It is exceedingly difficult to outline properly the clinicalconsequences and therapeutic attitudes to consider whensuch a variety of definitions are used. Therefore, a more pre-cise definition of dysplasia has been proposed for lesions ob-served in patients with IBD. According to this definition,dysplasia is used for lesions showing “unequivocal, noninva-sive (confined within the basement membrane), neoplastictransformation of the epithelium excluding all reactivechanges”. This definition implies that the lesion can be rec-ognised by microscopy (11). The definition stresses the na-ture and origin of the lesion, but its identification still relieson the recognition of morphological features resulting fromcytological and architectural changes in routinely processedand hematoxylin- and eosin-stained sections. The distinc-tion between neoplastic and reactive changes is clinicallyvery important but in practice not always easy. Reactivechanges appearing during healing are characterized by in-creased proliferation and the presence of less differentiated,immature cells, which differ from the normal cells in shape,cytoplasmic staining and nuclear aspect (Figure 1). This may

672 Can J Gastroenterol Vol 13 No 8 October 1999

Geboes and Rutgeerts

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render the differential diagnosis with genuine dysplasia diffi-cult. The presence of inflammation rather orients toward re-active changes because it is more commonly found in areas ofepithelial damage and, hence, reactive changes. Duringhealing, proliferation as indicated by the presence of mito-ses, must remain within the normal proliferative compart-ment, the location of which is well defined in thegastrointestinal tract. Mitoses occurring in an aberrant loca-tion are abnormal. Therefore, although the criteria are de-fined more precisely, the recognition of dysplasia stilldepends on observation in routine microscopy and interpre-tation of the findings. This partly explains the interobserverdifferences found in various studies (12,13).

When a biopsy is diagnosed as positive for dysplasia, a dis-tinction is made between different grades of severity. The le-sions are subdivided into three categories (mild, moderateand severe) or two categories (low grade and high grade)based on the severity of the neoplastic alterations (11). Ingeneral, it has been shown that interobserver agreement isbetter for high grade dysplasia.

When a biopsy is diagnosed as negative for dysplasia, itmust be realized that dysplasia in IBD usually has a patchydistribution throughout the colon, leading to problems withsampling error. Even if 20 to 40 biopsies are taken, less than0.1% of the colorectal mucosa is sampled (14). Still, accu-mulated experience from several prospective studies showsthat six to 10 different biopsies from different sites are suffi-cient to detect significant dysplasia (15).

The same definition of dysplasia was later applied to otherconditions of the gastrointestinal tract that carry an in-creased cancer risk, such as Barrett’s esophagus, and to thesquamous epithelium of the esophagus. The natural historyof dysplasia and its relation with carcinogenesis have beenstudied in these conditions, and these findings can aid in theunderstanding of what is happening in IBD-related dyspla-sia.

DIFFERENTIAL DIAGNOSISOverall, the major differential diagnosis when consideringdysplasia in a patient with IBD is the differential betweengenuine dysplasia and reactive lesions, mainly due to repairwith or without inflammation. Follow-up studies haveshown that there are also a few other special conditions withdifferential diagnoses that are clinically important. Severalstudies have looked into the correlation between the endo-scopic features of dysplasia associated with IBD and the mi-croscopic diagnosis of dysplasia. In general, it appears thatIBD-associated dysplasia can show no macroscopic lesions orcan appear as a flat lesion, as sessile-type polyps or as raisedplaque-like lesions referred to as dysplasia-associated lesionsor masses (DALMs) (16). Surveillance studies have shownthat a distinction has to be made between IBD-related dys-plasia, especially the polypoid or raised type, and a sporadicadenoma occurring in IBD. While the latter is unequivocallya neoplastic and hence a dysplastic lesion, its development isunrelated to the underlying IBD. The clinical distinction be-tween IBD-associated dysplasia, especially the polypoid dys-

plastic lesions, on the one hand, and sporadic adenomas onthe other hand, is extremely important because the formeroccur as a result of IBD, and their presence is an indicationfor colectomy because of a higher association with cancer,whereas the treatment of sporadic adenomas is simplepolypectomy. The differential diagnosis between these twotypes of neoplastic lesions, which both can occur in IBD, isbased on a variety of clinical and pathological features. Spo-radic adenomas are more common in older patients havingno disease activity and a relatively short disease history; in-flammation of the lamina propria is less common. Examina-tion of samples obtained in the mucosa surrounding theelevated lesion can help to exclude a DALM and to confirmthe diagnosis of a sporadic polyp. Pedunculated lesions foundin a dysplasia-free surrounding mucosa should be handled asin noncolitis patients (17,18).

Since the introduction of the definition of dysplasia as aneoplastic lesion and the development of standard criteriafor the diagnosis and grading by the Dysplasia Study Groupin 1983, knowledge on IBD has greatly increased and treat-


Dysplasia in IBD

Figure 1) Crohn’s disease regenerative lesion. The cells lining the cryptshow stratification of the nuclei, but in the upper part of the crypt the cellsbecome more cuboidal and on the surface they have an attenuated aspectwhere they cover a denuded area (hematoxylin and eosin, magnification�315).

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event in UC-associated CRC, while it may occur late in he-reditary nonpolyposis CRC (Figure 3). Interestingly, LOH ofthe p53 gene is often detected in tissue containing aneuploidcell populations, suggesting that aneuploidy precedes p53

LOH in UC (29). These data indicate that different path-ways may lead to the development of cancer, although thedifferences are probably small.

Morphologically, tumour development follows the ade-noma to dysplasia to carcinoma sequence. The genetic al-terations also occur in a certain preferred order, but thisorder is not necessarily always the same, and although the or-der of mutation can have a critical impact on the morpho-logical behaviour (as with ras and APC mutations, which areassociated with increased proliferation) it does not, by neces-sity, have this impact. In other words, the mutations associ-ated with tumour progression do not necessarily determinethe morphological appearance of a lesion. This can partly beexplained by the function of the proteins coded for by theoncogenes or suppressor genes. Activation of the ras genesleads to signal transduction, which induces a cascade ofevents that are thought normally to have a role in prolifera-tion and differentiation. Mutation can lead to continuoussignal transduction, even in the absence of an externalstimulus, and induce continuous proliferation, resulting in ahyperplastic (increase in cell number) lesion such as an ade-noma. The p53 protein is involved in the control of the tran-sit from the G0/G1 phase of the cell cycle to the S1 phase.Cells accumulating at the transition are primed for cell deathby apoptosis. This is less reflected in the morphology. Thisdifference in morphological consequences is illustrated byp53 mutations, which seem to be an early event in cancer de-veloping in the squamous esophagus and in Barrett’s esopha-gus as shown by the common expression of mutant p53 innormal squamous epithelium in cancer-bearing esophagi andin metaplastic columnar cells in Barrett’s esophagus (30,31).In sporadic CRC, it is a rather late event; hence, expressionof the mutant p53 may be negative in sporadic adenomas,while in UC- and Crohn’s disease-associated cancer, it maybe an early event and thus often present in dysplasia, even inthe low grade forms (29,32) (Figures 4,5). In general, it,therefore, appears that the same genetic defect can beexpressed before or after the alterations in cell shape and sizeand, therefore, before or after dysplasia can be recognized byroutine morphology. In other words, the genetic defects as-sociated with carcinogenesis related to cell proliferation andcell death, inducing alterations in proliferation, do not nec-essarily occur at the same moment as dysplasia (also implyingalterations in shape and architecture). Neither are they nec-essarily or constantly present.

DYSPLASIA AND GENETIC DEFECTSIN THE CONTROL OF TISSUE STRUCTURE

Cancer development is associated with defects in genes con-trolling cell proliferation and cell death but also with defectsof other important genes. Aberrant expression of proteinsand abnormalities in genes coding for proteins involved inthe preservation of cell shape and cohesion such as cy-

tokeratins, CD44 and e-cadherin have been reported inepithelial dysplasia and in many cancers. Cytokeratins aremembers of a large family of proteins that compose the inter-mediate filaments in the cytoplasm of most, if not all, epithe-lial cells. The intermediate filament system and itsassociated proteins represent a chain of molecular connect-ing links between the nucleus and the cell surface. They areimportant for tissue structure and integrity. The e-cadherinsare adhesion molecules. They are epithelial proteins thatplay a key role in the organization and maintenance of theepithelial structure. They mediate cell-cell adhesion. Ab-normalities in the structure or loss of these proteins, due togenetic defects, result in changes in cellular shape and size(cytology) and in defects in cell cohesion (architecture).This is illustrated by studies of the squamous esophageal epi-thelium. Dysplasia of the squamous esophagus is character-ized by downregulation of cytokeratin mRNAs, which arespecific for the differentiated normal esophageal epitheliumand by the upregulation and protein expression of cytokera-tin mRNAs and proteins, not present in the normal esophag-eal epithelium but characteristic of simple epithelia. The


Dysplasia in IBD

Figure 3) Dysplasia in ulcerative colitis. A Endoscopic colonic biopsiesstained with hematoxylin and eosin. Inflammation is prominent in bothsamples, but the architecture is more disturbed and the epithelial liningshows cytological abnormalities indicative of dysplasia in the sample on theright (hematoxylin and eosin �125). B Serial section stained withantibodies directed against p53 showing clear nuclear positivity in thesample on the right (immunoperoxydase, magnification �125)

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normal vertical migration of esophageal cells throughout theepithelium, characteristic for the normal esophagus and il-lustrated by a sequential expression of different cytokeratinpairs, is completely changed in dysplasia. The changes aremore prominent in high grade dysplasia (33,34).

CD44 is a broadly distributed transmembranous glycopro-tein acting as a cell adhesion receptor. Its major ligand, hya-luronan, is a common component of the extracellularmatrix. Various isoforms of the molecule have been de-scribed (35). They show variations in the extracellular partof the molecule, enabling the cells to contact further ligandsin addition to or instead of those mentioned above. Expres-sion of the CD44 v6 isoform has been described in colorectaladenomas, simultaneously with changes in the p53 tumoursuppressor gene (36). Changes in CD44 isoform expressionhave been reported in IBD. The investigations were mainlycarried out for diagnostic purposes to find markers allowing adifferential diagnosis between Crohn’s disease and UC (37).This hypothesis has not been confirmed. Instead it has beenshown that the proliferation index (% of positive cells), asassessed using immunohistochemistry and MIB1 as a markerfor proliferation, was dramatically increased in CD44

v6-positive crypts in UC and Crohn’s disease, comparedwith v6-negative crypts (38).

Adhesion molecules such as e-cadherins are involved incell signalling, differentiation and migration, and are relatedto polarity. Loss of polarity is one of the features used to diag-nose dysplasia. Reduced expression of e-cadherin has beenreported in UC and Crohn’s disease. It was suggested thatthe changes may be involved in promoting cell migrationduring epithelial restitution (39). The expression of e-cad-herin is also often altered in tumours (40). A selective losshas been noted in poorly differentiated tumours, and it hasbeen suggested that e-cadherin may act as an invasion-suppressor gene. Loss of e-cadherin expression is also foundin UC-associated cancers, but there is no difference whenthe data are compared with those obtained in sporadic can-cers (40).

The microscopic features on which a routine diagnosis ofdysplasia is based may be related to neoplasia-associated de-fects in genes in control of proteins involved in the mainte-nance of cell shape and cohesion, rather than to defects ingenes in control of cell proliferation or, more probably, toboth. In addition, development of dysplasia may further be



Figure 4) Dysplasia in Crohn’s disease. A Small intestinal biopsies with irregular villous architecture. The epithelial cells lining the villi are partially welldifferentiated. Some crypts show stratification of the nuclei extending towards the surface indicative of dysplasia (hematoxylin and eosin, magnification�125) B Semiserial section stained with antibodies directed against p53 showing clear nuclear positivity (immunoperoxydase, magnification �125

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influenced by growth factor-receptor pairs such as epidermalgrowth factor and epidermal growth factor receptor.

THE MORPHOLOGICAL DIAGNOSISOF DYSPLASIA AND THE USE OF

ADDITIONAL TECHNIQUESA search for genetic alterations to define dysplasia better canoffer support for the diagnosis if positive, but a negative find-ing does not exclude the possibility of dysplasia. Further-more, the results obtained with additional techniques mustbe interpreted with caution. Absence or decrease of e-cad-herin protein expression occurs in UC-associated CRC andin sporadic CRC. However it is not constantly present in allUC-associated cancers and has been observed also in benignulcerative lesions in UC (39,40).

Dysplasia and the genetic defects associated with cancerdevelopment are different phenomena identified with en-tirely different techniques. Dysplasia is a complex phenome-non, with multiple factors involved in its development. Thesearch for genetic defects using additional techniques is usu-ally limited to one specific marker. While a combination ofroutine morphology and new techniques for additionalmarkers can help to identify dysplasia, the search for addi-tional markers itself can only support a diagnosis of dysplasiaif positive, or help identify a cancer risk in patients in whomroutine morphology fails to detect dysplasia. How importantthe cancer risk is when aneuploidy is found or when p53 ex-pression is detected remains to be determined.

CLINICAL SIGNIFICANCE OF DYSPLASIAWhile both a positive diagnosis of dysplasia and a positivep53 expression indicate an increased cancer risk, they do notallow the magnitude of the risk to be assessed. Low grade dys-plasia itself is the earliest morphologically recognizable formof neoplastic transformation. Its natural history is not pre-cisely known. Yet it may not only be a precursor of cancer. Inpractice, dysplasia is often already associated with invasivecancer and, hence, is a marker of cancer. This is demon-strated by studies comparing biopsies and subsequently ob-tained resection specimens (41,42). The difference betweenthe findings on endoscopic biopsy and in a surgical specimenis explained by the sampling problems of endoscopy. Thefinding of genuine IBD-associated dysplasia, therefore,clearly has clinical implications – either control and regularfollow-up of the patient, or treatment, which in practicemeans surgery.

CONCLUSIONDysplasia is a lesion that can be recognized with morphologi-cal techniques. To be used properly, the term ‘dysplasia’needs to be defined adequately, with regard to both the na-ture of the lesion and the standard criteria used for its recog-nition. Dysplasia in IBD is defined as an unequivocallyneoplastic but noninvasive lesion. This implies that it is theearliest step in the multistep process of carcinogenesis thatcan be identified with morphological techniques. Conse-quently, such a lesion necessitates an appropriate clinical re-action. The clinical consequences depend on the age and

general condition of the patient and the severity of the dys-plastic lesion. A proper diagnosis of dysplasia, especially lowgrade dysplasia is not always easy and the pathologist must beaware of the consequences of the diagnosis (43). Because ofthe diagnostic difficulty, in view of the interobserver varia-tions, and given the clinical consequences, a second opinionmay be indicated even for low grade dysplasia. The differen-tial diagnosis with pseudodysplasia during treatment andwith sporadic adenomas is difficult, but clinically extremelyimportant. The histological evolution of cancer in UC is dif-ferent from that of sporadic tumours (44). The use of addi-tional techniques can help to solve the problem and cansupport the diagnosis. Yet aneuploidy and molecular changesdue to genetic defects can either be absent or appear early orlate in the transition from the normal cell phenotype towarddysplasia and invasive cancer. Because of the possible timedifference between the occurrence of genetic defects associ-ated with carcinogenesis and the development of dysplasia,and given the fact that the appropriate techniques measurechanges other than dysplasia, the results of both the routinemorphology and the special techniques are not always con-cordant. For these reasons, and because of practical avail-ability and costs, the simple morphological recognition ofdysplasia in endoscopic biopsies remains important for themanagement of the cancer risk in IBD.


Dysplasia in IBD

Figure 5) Sporadic adenoma from a noninflammatory bowel diseasepatient stained with antibodies directed against p53. Nuclear positivity ispresent in only a limited part of the neoplastic adenomatous glands andcells (immunoperoxydase, magnification �125).

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