Role of Endoscopy in Ulcerative Colitis

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Introduction

The need to formulate a correct diagnosis of ulcerative colitis (UC), based also on histopathological findings, for differential diagnosis from Crohn’s disease (CD) and to establish site and extension of the disease are indications for colonoscopy in UC patients. In patients with certain diagnosis, colonoscopy is the gold standard to identify preneo- plastic lesions (dysplasia) during surveillance for colorectal cancer (CRC), which is more common in patients with UC than in the general population (Table 1).

Table 1.Colonoscopy role in management of ulcerative colitis (UC)

Diagnostic validation Extension of UC

Conventional medical therapy failure

Complication onset (stenosis, dysplasia, cancer)

Diagnosis

A colonoscopy with visualisation of the entire colon and terminal ileum allows a correct differential diagnosis from CD in 85–90% of patients, but in 10–15%

of patients, only a diagnosis of indeterminate colitis can be established [1]. In severe disease, endoscopic examination must be limited (proctosigmoidoscopy), with careful insufflation, due to high risk of perforation and toxic megacolon.

Active Disease

Endoscopic lesions change with inflammation degree. In mild disease, the mucosa is hyperaemic, with abnormal vascular pattern; in moderate disease, vascular pattern vanishes and the mucosa is friable, easily bleeding at instrument touch, with superficial ulcerations. Severe disease is characterised by spon-

taneously bleeding deep ulcerations, with mucopuru- lent exudate. Characteristically in UC, the rectum is involved at all times and, differently from CD, lesions are extended continuously from rectum to proximal colon. Therefore, inflammation can involve the sigma and rectum (proctosigmoiditis), extend to the splenic curve (left-side colitis) or affect the entire colon (extensive colitis). Before colonoscopy the patient’s pharmacological history should be obtained because the use of medical enemas can normalise the rectal mucosae and induce erroneous CD diagnosis.

Ileal lesions are characteristic of CD and represent major macroscopic criteria to differentiate UC from CD. In 17% of patients with pancolitis, severe inflammation can induce incompetence of the ileocecal valve and consequent faecal reflux, causing inflammation (backwash ileitis). Generally, extension and severity of colitis are correlated to severity of ileum inflammation, even if 2% of backwash ileitis is associated to severe left-side colitis or mild extensive colitis. It seems that other pathogenetic factors are impli- cated to backwash ileitis (infections, bacterial over- growth, reaction to drugs, etc.). Backwash ileitis does not seem to correlate with increased CRC development risk nor to higher incidence of complication after proctocolectomy with an ileal pouch [2].

In course of the first colonoscopy biopsies for histopathological definition of colitis type are necessary; in any cases, only biopsies can distinguish idio- pathic colitis from infectious colitis. Biopsies must be taken from inflamed mucosae, healthy mucosae and ileum since real UC extension and existence of microscopic inflammation must be evaluated because therapy and prognosis can change accord- ingly. A new approach to microscopic inflammation is confocal endoscopy (see below), which allows targeted biopsies.

Silent Disease

During silent disease (remission phase), haustrae are reduced and the colon is tube like; characteristic

Role of Endoscopy in Ulcerative Colitis

Giampaolo Angelini, Laura Bernardoni

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lesions are pale and sometimes granulose mucosae (atrophy) is apparent and there is a loss of vascular pattern and presence of pseudopolyps. The so-called inflammatory polyps are present in acute and quiescent disease and are composed of regenerating mucosae and inflammatory cells without dysplastic epithelium. Therefore, they do not degenerate to CRC. The use of A video capsule is very limited in UC. It can play a marginal role in indeterminate colitis, showing unknown lesions in the small intestine that can contribute to a diagnosis of CD [3].

Disease Activity

In clinical practice, Truelove-Witts index is used to establish disease activity, but many endoscopic scores are used to measure UC activity [for example, St. Mark’s index, UC disease activity index (UCDAI), Mayo score), but endoscopy gives little additional information to clinical indexes of disease activity in UC. In clinical practice, it seems appropriate to treat these patients on the basis of symptoms [4, 5].

Follow-Up of US

After correct diagnosis and obtaining remission maintained by correct medical therapy, a second colonoscopy within 8 years from the beginning of the symptoms, is indicated only in case of relapse not responsive to therapy [6–9]. Refractory disease can be caused by viral infection (most commonly by cytomegalovirus), primarily in patients on immuno- suppressant maintenance therapy. In this case, the endoscopist has a front-line role taking biopsies from the bottom of the ulcers, where CMV implant, during proctosigmoidoscopy.

After 8 Years from the Beginning

The main role of colonoscopy during follow-up of UC is screening and surveillance for CRC. The life- time prevalence of CRC in patients with UC is estimated to be 3.7% and 5.4% among those with total colitis. Rates are higher in patients with longstanding disease, and the cumulative probabilities at 10, 20 and 30 years increase to 2%, 8% and 18%, respective- ly. Compared with age-matched members of the general population, the relative risk of cancer is 20% for extensive colitis and 4% for left-side colitis [10]. The main risk factors for CRC in patients with UC are reported in Table 2.

Before 8 Years from the Beginning Disease Standing

Disease standing is an independent risk factor for CRC development in patients suffering from UC.

There is no standard definition for the duration of UC. Although some studies define duration based on the date of radiological, endoscopic or histological diagnosis, a preferred approach is to define it in rela- tionship to the onset of UC-like symptoms. Since the risk of CRC becomes greater than in general population after 8–10 years from disease onset [12], the Crohn’s and Colitis Foundation of America (work- shop: “Colon cancer in IBD: science and surveillance”, Palm Harbor, Florida, March 2000recom- mends that a screening colonoscopy be performed 8–10 years after onset of symptoms attributable to UC to redefine extension and cutoff dysplasia. Then, a regular surveillance program should be carried out.

Anatomic Extension

As disease standing it is an independent risk factor for CRC, extension should be defined by both endoscopic and histological evaluation, whichever reveals more extensive involvement, not with radiological images since cancer and dysplasia can arise in areas of the colon that show histological evidence of disease even without macroscopic abnormalities [13].

Primary Sclerosing Cholangitis

All patients with primary sclerosing cholangitis (PSC) without prior diagnoses of irritable bowel disease (IBD) should undergo a colonoscopy to deter- mine their status. This procedure should include biopsies from normal-appearing mucosae because microscopic evidence of colitis may not be visually apparent. For patients suffering from IBD, screening and subsequent yearly surveillance should begin at the time of PSC onset.

Table 2.Risk factors for colorectal cancer (CRC) in ulcerative colitis (UC) patients [11].

Disease standing Anatomic extension

Positive family history for CRC Age at onset of UC

Severe or chronic inflammation Primary sclerosing cholangitis

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Age of Onset

Although there is some evidence to support a higher relative risk for CRC among UC patients diagnosed at a young age [12], there is insufficient evidence to support starting screening and surveillance before 8 years of disease onset.

Positive Family History of CRC

This is an additional risk factor for development of CRC in patient with UC [14], but there is insufficient evidence to warrant a closer follow-up.

In a recent study, Rutter et al. [15] demonstrated that some endoscopic lesions were correlated to higher risk of CRC development and, on the con- trary, that normal endoscopy testified a low risk of neoplasia. Mainly, pseudopolyps were correlated to higher risk of CRC development not because of direct degeneration but because they are an expression of severe and constant inflammation. Some drugs may modify risk of development of CRC; aminosalicylate use, perhaps folic acid intake and ursodeoxycholic acid in the subset of colitis patients with PSC have been suggested to be cancer chemopreventive agents [16, 17]. A screening colonoscopy must be done to rule out dysplasia or cancer after 8–10 years from the onset of the disease. The accuracy of intestinal washout is very important because, in these patients, minimal lesions can be in situ carcinoma.

The cornerstone of endoscopic surveillance in UC is dysplasia, which is defined as unequivocal neoplastic alteration of the colonic epithelium. Dysplasia represents the histological manifestation of wide- spread chromosomal instability caused by the effects of persistent inflammation. Most cancers in colitis are preceded by dysplasia, and approximately 75% of cases have coexisting dysplastic change elsewhere in the colon. The detection of dysplasia in colitis is used as a clinical marker of imminent or established carcinoma. During examination, multiple biopsies must be taken, even on normal mucosae, to assess extension increase of UC [18].

After screening, patients with UC must begin a regular surveillance program (Fig. 1). Patients with extensive colitis or left-side colitis who have a negative screening colonoscopy should begin surveillance within 1–2 years. After 2 negative examinations, the next surveillance colonoscopy can be performed every 3 years until UC has been present for 20 years.

At that time, consideration should be given to short- en the surveillance times to 1–2 years since CRC risk increases with longer duration of colitis. Patients with PSC should undergo yearly surveillance.

Patients with proctosigmoiditis, who have little or no

increased risk of CRC compared with the general population, should be managed according to standard CRC prevention measures as defined in guide- lines [11].

Screening colonoscopy must be performed during quiescent UC because the presence of severe inflammation can cause an erroneous histological differential diagnosis from dysplasia. Standard examination must include the entire colon and the collection of 4 random biopsies every 10 cm of mucosae since it has been estimated that 33 biopsies are required to pro- vide a 90% chance of finding the highest degree of present dysplasia [19]. In UC, dysplasia on flat mucosae is distinguished by dysplasia associated to lesions or mass (DALM) because there is a significant major risk that these harbour cancer, even if a recent study showed that in 90% of patients a scrupulous colonoscopy can detect dysplastic lesions even on flat mucosae [20].

New Endoscopic Techniques

New endoscopic techniques are being introduced to improve early identification of even minimal lesions and to take targeted biopsies in suspicious areas.

These techniques do not replace colonoscopy but are second-level examinations [21].

Fig. 1.Follow-up in UC

8-10 years Onset of symptoms of UC

Surveillance program (colonoscopy every 1-2 years) Primary sclerosing

cholangitis Screening colonoscopy

I and II colonoscopy negative

Colonoscopy every 3 years to the 20° year of UC

Yearly colonoscopy

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Chromoendoscopy

Endoscopic dye-spraying can improve dysplasia detection [7, 19]. This procedure involves the appli- cation of a mucosal stain or pigment, usually by injection through an endoscopic spray catheter.

Chromoendoscopy improves the detection of minimal colonic lesions, raising the sensitivity of the endoscopic examination and, once a lesion is detect- ed, can allow lesion characterisation, increasing the specificity of the examination [21–24]. There are 3 general classes of stain:

– Contrast dyes (for example, indigo carmine 0.1%):

These coat the colonic mucosal surface and nei- ther react with nor are absorbed by it. When dye is sprayed on the surface, groove patterns becomes evident and so mucosal lesions are highlighted.

– Absorptive dyes: These are absorbed by different cells to different degrees. Methylene blue 0.1%

after few minutes avidly stains noninflamed mucosae but is poorly taken up by areas of active inflammation and dysplasia.

– Reactive dyes: These react with epithelium or mucosal secretion, producing detectable colour change.

Colour use seems to be safe. The indigo carmine is poorly absorbed from the gastrointestinal tract.

There is a theoretical risk of allergic reaction, but this has not been reported with intraluminal use.

A recent study suggests that methylene blue can cause DNA damage after chromoendoscopy in patients with Barrett’s oesophagus.

Description of Procedure

On insertion, all faecal fluid should be aspirated and adherent stool washed off to ensure optimal mucosal views. Any abnormalities seen on insertion should be biopsied or removed, as they may not be easily identi- fied on extubation. When the cecal pole has been reached, intravenous drugs (scopolamine 20 mg or glucagon 1 mg) should be given to reduce spasm and haustral-fold prominence. Adequate air insufflation is necessary. A dye-spray catheter is inserted down the

instrumentation channel and the tip protruded 2–3 cm, and an assistant can spray the stain with a syringe.

Spraying should be done in segments of 5–15 cm. Once a segment has been sprayed, excess dye must be suc- tioned and mucosal examination begins; it is necessary to wait few seconds for indigo carmine to settle into the mucosal contours; methylene blue takes about 60 s to be absorbed. Once this segment has been examined, the next segment is sprayed and so on until the anal mar- gin. On average, 60–100 ml of solution is required to spray the entire colorectal mucosa. Suspicious areas should be photographed, biopsied and the site endo- scopically resected or tattooed if necessary. Patients with multiple postinflammatory polyps present a dilemma because the mucosa is not smooth, making dysplasia detection difficult. The colonoscopist must remain alert for any polypoid lesion that does not have a smooth surface and should take biopsies.

Magnifying Colonoscopy

New-generation colonoscopes with lens system on the tip enlarge the imagine up to 140 times [25–27].

Magnifying colonoscopes can show anatomic details to discriminate inflammatory from neoplastic lesions and to establish inflammation extension [27, 28], which previously was detectable only by histopathological examination. It has been reported that microscopic disease activity can predict relapse in patients with UC and so influence the treatment plan.

By matching chromoendoscopy and magnifying colonoscopy, it is possible to obtain a very detailed mucosal examination, and even to distinguish polyp types (pseudopolyp, hyperplastic and adenomatous).

Kudo et al. [29] confirmed the feasibility of applying the “pit patterns” of the colonic polyp to distinguish them via magnifying colonoscopy and indigo carmine dye contrast (Table 3) [28, 30].

Confocal Endoscopy

Today it is possible to obtain in vivo microscopic imagines by introducing a catheter into the operative

Table 3.Kudo et al classification for “pit pattern” [29]

Non neoplastic polyp Neoplastic polyp

Type I Normal round pit

Type II Small or large asteroid pit

Type III s Smaller than normal tubular or round pit

Type III l Larger than normal tubular or round pit

Type IV Dendritic or gyrous-like pit

Type V Nonstructural pit

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endoscopic channel [31, 32]. A fluorescent contrast agent is used to achieve high-contrast images. Fluo- rescein used systemically is preferred to acriflavine, tetracycline or cresyl violet used topically, since these agents have mutagenic potential cell’s structure in a dedicated monitor. This new technology should allow histological diagnosis during conventional colonoscopy, but at the moment, accuracy is no bet- ter than 60%.

Management of Abnormal Findings

A finding of histologic lesions “indefinite for dysplasia”, confirmed by 2 expert pathologists, warrants strict surveillance with repeat endoscopy within 3 months [33]. A finding of high-grade dysplasia indi- cates total colectomy because of the high risk of synchronous or metachronous CRC [34, 35]. Manage- ment of low-grade dysplasia is uncertain because it can progress to high-grade dysplasia or cancer in approximately 35–50% of patients within 5 years.

Hence, 20% of patients with low-grade dysplasia have a CRC diagnosed at prophylactic total colectomy.

Therefore, different therapeutic options should be considered. Prophylactic colectomy should be rec- ommended if the number of specimens is poor or in multifocal dysplastic areas. If the patient declines prophylactic colectomy, careful surveillance should be carried out by a colonoscopy with adequate biopsies every 3–6 months. Negative sequential colonoscopy should not encourage patient or physi- cian, and surveillance must continue every 6 months [33].

In the case of polyps in UC mucosae [adenoma- like mass (ALM)], polypectomy is indicated and, moreover, biopsies should be taken in the surround- ing area (for separate examination). If those are negative for dysplasia, surveillance should be carried out every 6 months; however, if dysplasia is present on the mass or in the adjacent area, colectomy is indicated because of the high risk of synchronous CRC [11, 19, 36–38]. If the polyp is on either macroscopi- cally or microscopically healing areas, follow-up is similar to those of sporadic adenoma.

Stenosis

Restorative proctocolectomy with ileal pouch–anal anastomosis is the surgical treatment of choice for patients with medically refractory UC or UC with dysplasia. A well-known complication of surgery is the stricture of the pouch outlet (pouch-anal anastomosis) or pouch inlet (the junction of neoterminal ileum and pouch). Both can benefit from endoscopic

balloon dilatation associated with topical injection of long-acting steroids. This procedure appears safe and effective in treating pouch outlet and inlet anastomosis and can avoid or delay surgery [39].

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