Dysplasia in inflammatory bowel diseases

Digestive and Liver Disease 45 (2013) 186–194

Contents lists available at SciVerse ScienceDirect

Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld

Review article

Dysplasia in inflammatory bowel diseases Claudia Mescoli a , Laura Albertoni a , Renata D’incá b , Massimo Rugge a,∗ a b

Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Italy Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy

a r t i c l e

i n f o

Article history: Received 24 May 2012 Accepted 18 July 2012 Available online 10 September 2012 Keywords: Colorectal cancer Dysplasia IBD Intraepithelial neoplasia

a b s t r a c t In both Crohn’s disease and ulcerative colitis, the secondary prevention of colorectal cancer basically relies on the histological detection of dysplasia. In inflammatory bowel diseases, dysplasia identifies the subgroup of patients eligible for stricter surveillance (or prophylactic colectomy). In clinical practice, a number of issues may influence the benefits of clinico-pathological surveillance for inflammatory bowel disease patients with dysplasia, including: sampling errors, inconsistent biopsy assessments, patients’ compliance with follow-up requirements, and how heath care is organized. Even in such a multifaceted context, it has been demonstrated that dysplasia surveillance is effective in reducing colorectal cancer-related mortality and morbidity. This paper focuses on current issues concerning the histological assessment of inflammatory bowel disease-associated dysplastic lesions. © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Colorectal cancer in IBD: prevalence, incidence and risk factors The first case of adenocarcinoma arising in ulcerative colitis (UC) was reported in 1925 (Fig. 1) [1]. Although inflammatory bowel diseases (IBDs) contribute only 1–2% to all cases of colorectal cancer (CRC), the cancer-related mortality rate in IBD patients is approximately 15% [2,3]. In patients with a more than 40-year-long history of IBD, the cumulative probability of developing CRC has been judged by some to be as high as 60% [4], while others associate IBD with a cancer risk comparable with that of the general population: the reasons for these diverse findings include differences in how cases are defined and in study design, ethnic diversity, host-related and environmental co-factors, and referral centre biases [5,6]. 2. Chronic inflammation as determinant of IBD-associated cancer risk A case–control study conducted by Rutter et al. on 68 UC patients, showed that inflammation (as assessed at both colonoscopy and histology) is associated with increased CRC risk (OR for endoscopy = 2.5, p < .001; OR for histology = 5.1; p < .001)

∗ Corresponding author at: Chair of the Surgical Pathology Unit, Department of Medicine, University of Padova, Istituto Oncologico Veneto-IRCCS, Via Aristide Gabelli, 61, 35121 Padova, Italy. Tel.: +39 049 8218990; fax: +39 049 8272277. E-mail address: [email protected] (M. Rugge).

[7]. On this point, however, it is relevant to report the Mathy et al. experience who found that CRC may arise in endoscopically normal (but histologically involved) colon mucosa [8]. Based on their results, the authors concluded that – rather than endoscopy – histology is a better determinant of disease extent in evaluating the disease-associated cancer risk. In a study involving 418 UC patients, Gupta et al. [9] correlated the histology score of inflammation to cancer development. On the follow-up, among the 65 patients who developed neoplasia (LGD, HGD, or carcinoma), 17 featured “advanced” lesions (defined as either HGD or cancer). A significant association was found between inflammatory score and advanced lesions (HR = 3.0; 95%CI = 1.4–6.3); such a significant relationship was not confirmed when also low-grade dysplasia was included among the adverse outcomes. Taking all the available information together, even with minor discrepancies, consistent data support the oncogenetic impact of chronic inflammation (and IBD, in particular) in colorectal mucosa. Evidence has been provided that, in IBD, several molecular pathways are dysregulated, even in absence of any histology evidence of dysplasia or cancer. Reactive oxygen and nitrogen species produced by inflammatory cells likely play a role by interacting with key genes involved in carcinogenic pathways, such as p53 and DNA mismatch repair genes [10]. Thus, the “adenoma–carcinoma” sequence of sporadic-cancers becomes the “inflammation–dysplasia–carcinoma” sequence in IBD. On a clinical level, the link between inflammation and IBD-related neoplasia relies on the well known correlation between cancer risk and disease activity, extent, and duration. Such a relationship is further

1590-8658/$36.00 © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.dld.2012.07.013

C. Mescoli et al. / Digestive and Liver Disease 45 (2013) 186–194

187

for dysplasia and cancer in UC: they calculated that the cumulative cancer incidence was 2.5%, 7.6%, and 10.8% after 20, 30, and 40 years, respectively. Linear regression suggested that the incidence of CRC declined over the course of the study, supporting a role for surveillance in reducing the risk of CRC [17]. The most recent meta-analysis on population-based studies associated UC with a 2.4-fold risk of CRC, which represents an overall rate of CRC of 1.6% (including sporadic cases) during the first 14 years of follow-up for UC patients [18]. The declining trend in the incidence of CRC among UC patients gives the impression that combining the control of UC-related inflammation with surveillance strategies is highly effective in CRC secondary prevention and suggests that appropriate levels of vigilance should be maintained in high-risk patient populations. 4. CRC risk in Crohn’s disease

Fig. 1. The historical scientific paper by Crohn and Rosenberg [1] reporting “. . .a malignant degeneration of a late stage of polypoid ulcerative colitis. . .” (digital image combining page 220 and page 226 of the original publication).

supported by the evidence of the chemopreventive benefit conferred by 5-aminosalicylates and other anti-inflammatory drugs [11]. 3. CRC risk in ulcerative colitis In a meta-analysis of 41 studies (concerning 54,478 UC patients and 1698 cases of CRC), Eaden and colleagues [12] found an overall prevalence of CRC of 3.7% (rising to 5.4% in pancolitis patients). On pooling the results obtained in studies that mentioned the duration of the disease by decade, the authors calculated that the cumulative probability of developing CRC was 2% after 10 years, 8% after 20 years, and 18% after 30 years of UC. These results were subsequently not replicated, however, in several population-based and referral-based studies, suggesting that either the risk has been declining over the last few decades or it is simply lower than was previously believed. In a large populationbased study with a follow-up of 19,655 person-years, Bernstein et al. reported a 3-fold increased risk of developing CRC of 2.75 [95%CI 1.91–3.97], 3 times higher than for the reference population [13]. These findings were basically consistent with those obtained in a Hungarian population-based study reporting a cumulative incidence of CRC of 0.6% after 10 years, 5.4% after 20 years, and 7.5% after 30 years of disease [14]. A smaller population study from Olmsted County (MN, USA) considered 378 UC patients diagnosed between 1940 and 2001 [15]. In a follow-up consisting of 5567 person-years, there were only 6 cases of CRC, yielding a 30year cumulative probability of CRC of 2% (not significantly different from that of non-IBD subjects). This picture was supported by a much larger Danish study (with 22,290 person-years of follow-up), which found no additional risk of CRC among UC patients (the 30year cumulative probability of CRC was 2.1%) [5]. Other recently reported figures suggest that the risk of colon cancer for people with IBD increases by 0.5–1.0% a year as of 8–10 years after diagnosis [16]. Rutter and colleagues from St. Mark’s Hospital prospectively collected the longest database (spanning 30 years) on surveillance

Fewer (and more debatable) data are available on the risk of CRC in Crohn’s diseases (CD) [19–21]. Assessing CRC risk in CD patients poses a number of methodological challenges, related mainly to the heterogeneous clinico-pathological nature of the disease: many patients may have no colonic involvement, and any colonic distribution is generally patchy; in addition, any segmental colectomy performed results in removing some of the colonic segments at risk. Gyde and colleagues claimed that the relative risk of CRC in Crohn’s colitis (CC) (with extensive colonic involvement) was 23.8 (compared to 4.3 in the general Crohn’s population) [22]. Greenstein and colleagues calculated the relative risk at 6.9 for CRC developing in isolated CC [23]. A Swedish landmark study associated Crohn’s disease with a different neoplasia risk according to the extent/location of the disease. In particular, the relative risk of CRC in colon-restricted disease was significantly higher than that of ileum-restricted disease (5.6 versus 1.0, respectively), while patients with ileo-colitis carried an intermediate risk of 3.2 [19]. A subset analysis also revealed that patients diagnosed before they were 30 years old carried a higher relative risk than patients diagnosed at an older age, and the risk for the former was much the same as for UC patients. A meta-analysis on twelve hospital- and population-based studies on the CRC risk in CD patients revealed an overall relative risk of 2.5, which rose to 4.5 when only patients with colonic disease were considered (in disease restricted to the ileum the risk did not differ significantly from that of the general population). The cumulative risk of CRC for all patients with CD, regardless of the disease’s distribution, was 2.9% after 10 years, 5.6% after 20 years and 8.3% after 30 years of disease [24]. Jess et al. performed a meta-analysis that only considered population studies: in the six papers that met the inclusion criteria the relative risk of CRC ranged from 0.9 to 2.2 (pooled risk = 1.9) [21]. The most recent paper on colorectal cancer screening/surveillance in Crohn’s colitis (n = 411 patients with long-standing CC during a 17-year period) detected neoplasia in 5.6% of the patients’ population [25]. 5. Comparing neoplastic risk between CC and UC patients Gillen and colleagues compared the risk of CRC among UK patients with extensive CC versus extensive UC [26], finding that the relative risk of developing CRC was 18 for CC and 19 for UC. This comparable risk was supported by a similar cancer risk after 22 years of disease (CC 7% versus UC 8%). Similar results were obtained in a large population-based Canadian study (the CCassociated CRC risk was 2.64; 95%CI = 1.69–4.12 as opposed to 2.75; 95%CI = 1.91–3.97 for the UC-associated CRC risk) [13]. According to available reports, the risk of developing CRC is basically much the same for CC and UC patients (with a similar extent of

188


disease) and in both cases it increases with: (i) duration of colitis, (ii) early age of IBD onset, (iii) extent of colonic involvement, (iv) severity of inflammation, (v) family history of CRC (among IBD patients with a first-degree relative who has/had CRC, the relative risk of CRC becomes 2.5 UC for UC and 3.7 for CC) [6], and (vi) primary sclerosing cholangitis (the absolute cumulative risk of CRC/dysplasia in this subset of patients has been estimated to be 9% after 10 years, 31% after 20 years, and 50% after 25 years of colitis) [27].

6. Dysplasia and CRC in IBD: clinical and pathological features More than 90% of cancers arising in IBD coexist with adjacent dysplasia [28–30], but dysplasia may also develop far from the invasive adenocarcinoma [28,30] and may be either isolated or multifocal (it is rarely diffuse) [28–31]. Compared with sporadic colorectal carcinoma (s-CRC), colitisassociated colorectal cancer (Ca-CRC) has several distinctive clinical features:

Ca-CRC affects individuals younger than s-CRC; Ca-CRC arises more frequently than s-CRC in flat (non-polypoid) dysplasia; Ca-CRC tends to be distributed more evenly throughout the colon; Ca-CRC tends to have a higher histological grade; Ca-CRC exhibits a mucinous/signet-ring histology most often than s-CRC; Ca-CRC has a higher rate of synchronous cancers (two or more), which reflects an inflammation-related cancer “field effect”; and the sequence of molecular events leading from dysplasia to invasive cancer differs between s-CRC and Ca-CRC [32].

7. Colitis-associated CRC: molecular pathways In the IBD setting, neoplastic transformation is a (multistep) sequence of genotypic and phenotypic events, and many of the molecular dysregulations occurring in s-CRC also play a part in colitis-associated carcinogenesis. The three molecular pathways of sporadic colon carcinogenesis (loss of heterozygosity [LOH], microsatellite instability [MSI], and CpG methylator phenotype [CIMP]) are consistently documented in colitis-associated cancers too. Distinguishing features have been documented in Ca-carcinogenesis, however, concerning both the timing and the frequency of the key genetic changes. Loss of APC function, which occurs early in s-CRC, is much less frequent (and generally late) in the colitis-associated dysplasia-tocarcinoma process. Conversely, LOH in p53 (a late occurrence in sporadic oncogenesis) occurs early in IBD (even in non-dysplastic mucosa). K-ras mutations are relatively uncommon in colitis-associated CRC and they are more frequently documented in sporadic (IBDassociated) adenomas with polypoid growth [33]. Suggestively, this low prevalence of K-ras mutations couples with the most usual flat phenotype of the IBD-associated CRCs. DNA methylation and microsatellite instability are early findings in IBD-associated neoplastic transformation. CpG island methylation (in several genes) seems to precede dysplasia and is more widespread in UC patients [32,34]. Ca-CRCs with microsatellite instability exhibit frequent BRAF but no KRAS mutations; patients are younger at the time of diagnosis and there is neither female predominance nor any right-sided predominance [35]. In UC patients with MSI-H CRCs, MSI may be demonstrated already 2–12 years before CRC is diagnosed in about 25% of cases [36].

8. Dysplasia detection in IBD Dysplasia (synonyms: intraepithelial neoplasia [IEN], or noninvasive neoplasia [NiN]), as assessed by conventional histology, remains the most reliable marker of cancer-prone IBD patients [37–42]. Dysplasia detection depends on several variables: (a) the frequency of colonoscopy and the technique used; (b) the quality and quantity of the biopsy samples obtained; (c) the endoscopist’s and pathologist’s expertise; and (d) the patient’s compliance with the recommended follow-up [43].

8.1. Dysplasia assessment: endoscopy-related issues (i.e. timing of endoscopy and biopsy sampling protocol) Surveillance colonoscopy relies on the ability to detect precancerous lesions (dysplasia) before cancer is unequivocally identified [42,44–48]. In general, surveillance colonoscopies should be performed when the disease is in remission (dysplasia is more difficult – or even impossible – to discover in areas of active inflammation). Different national and international gastroenterology societies have produced (basically similar) guidelines for CRC screening in IBD patients. They all recommend: (a) beginning regular surveillance 8–10 years after the onset of symptoms in cases of pancolitis, and after 15–20 years for left-sided disease; and (b) obtaining 2–4 random colon biopsy specimens every 10 cm with additional samples of any suspicious areas [2,47,49–52].

8.1.1. When to start surveillance International guidelines recommend systematic surveillance in patients with a history of 8–10 years of extensive UC, or 15 years of left-sided UC; earlier surveillance is not recommended. It has been shown, however, that IBD may have been considerably more or less long-standing before cancer is diagnosed. Specifically addressing this point in 149 Ca-CRC patients, Lutgens et al. [53] showed that the diagnosis of CRC is delayed or missed in a substantial number of patients, even when the surveillance guidelines are strictly followed. Taking the time of diagnosis as the entry point, 22% of their patients developed cancer before 8–15 years had elapsed. It is also worth noting that if the time of clinical onset of UC were used to calculate the surveillance schedule, 17–22% of patients would develop cancer before the start of the surveillance programme. Brackmann et al. specifically investigated the time elapsing between IBD onset (clinical symptoms) and CRC diagnosis: interestingly, in 12% of patients CRC was assessed less than 10 years after the onset of their IBD symptoms, and 21% within 10 years of their IBD diagnosis being confirmed [54]. In the same study, the patient’s age when they developed clinical IBD significantly predicted cancer onset [53]: the authors reported that the time to cancer was shorter in late-onset IBD, and cancers were detected in a more advanced stage. Karvellas and colleagues also found that CRC developed “more rapidly” among IBD patients diagnosed after 40 years of age [55]: among these late-diagnosed patients, the early onset of Ca-CRC could just result from a delayed IBD assessment [56,57]. Taken together, these features identify two subgroups of IBDassociated neoplasia: (i) a more common, multifocal (high-grade) dysplasia linked to early-onset IBD associated with active inflammation; and (ii) a much less prevalent monofocal dysplasia linked to late-onset IBD, with less severe inflammation and with an agerelated cancer risk similar to that of sporadic neoplasia [54]. These data might have major consequences for the timing of surveillance strategies.


8.1.2. Random versus targeted biopsies The number of biopsy samples to obtain for assessing/excluding dysplasia is controversial. Nearly all available guidelines recommend taking 2–4 random biopsy specimens every 10 cm along the full length of the colon, resulting in 40–50 samples. The rationale for this approach lies in a mathematical model: a typical biopsy sample represents less than 0.05% of the colon, so the probability of detecting dysplasia is 90% and 95%, respectively, when 33 and 64 random biopsies are obtained [58]. Since the distribution of neoplasia in UC shows a distal predominance, some experts suggest taking more biopsies in the distal recto-sigmoid region (e.g. approximately every 5 cm) [59]. Many gastroenterologists are either not fully aware of these recommendations or do not adhere to them, however, since recent data have shown that less than 10 biopsy samples are routinely obtained in more than 50% of cases [60]. This raises the question of why random biopsies are preferable to targeted biopsy sampling. Rutter et al. [61] and Rubin et al. [62] consistently demonstrated that up to 73–77% of dysplastic lesions and 89–100% of invasive cancers in UC patients are detectable endoscopically. In a group of 49 UC patients who underwent colonoscopy for secondary CRC prevention, Blonski et al. [63] found 58 dysplastic sites, the vast majority of which (88%) were detectable macroscopically. Applying magnifying endoscopy in 886 UC patients, dysplasia/early-CRC were characterized best by granular or nodular protruding mucosa (seen best after chromoendoscopy). Dysplasia was never found in normal-appearing mucosa after staining [64]. Rutter et al. [65] also found no dysplastic tissue in 2904 nontargeted biopsies. Based on these results, random biopsy sampling in unsuspicious mucosa hardly seems to be a priority and targeted biopsies have consistently qualified as a cost-effective alternative to randomly sampling IBD mucosa. Conventional (dye spraying) or virtual chromoendoscopy, and narrow-band imaging have further improved the reliability of endoscopy in early cancer detection [43,66], and random biopsies of apparently normal mucosa add nothing of value when compared with targeted biopsies [67–69]. Confocal laser endomicroscopy (CLE) has recently been suggested as a method to enable real-time in vivo microscopic images to be obtained for use in targeting biopsies. Given the costs of the hardware, the time taken to complete the procedure, and the expertise needed to interpret the images, the clinical impact of such a fascinating procedure remains largely questionable and CLE seems more appropriate for research than for clinical purposes [70–72]. 8.2. Dysplasia assessment: pathology-related issues (i.e. inter-observer variability) The histological assessment of biopsy specimens (from wherever they were obtained) is fundamental to patient management: it is ultimately the pathologist’s interpretation that distinguishes high-risk from low-risk patients and triggers recommendations to continue surveillance or opt for colectomy. The histological spectrum of dysplasia can be divided into three categories: negative for dysplasia, indefinite for dysplasia, and positive for dysplasia (distinguished as low-grade [LG-D] or high-grade [HG-D]) [39]. Although this system continues to be widely used, it has several well-recognized limitations, including its low intra- and inter-observer variability (even among experts) [39,40]. In both prospective and retrospective studies, inter-observer consistency in the histological assessment of dysplasia has ranged between 42% and 72%. [73–79]. In a more recent study, Lim et al. [79] found a kappa coefficient between ten pairings of five GIpathologists in the range of 0.6 (acceptable) to 0.39 (unacceptable). The agreement is obviously best when the two extremes of the histological spectrum of the lesions are considered (no dysplasia versus HG-D), while the diagnostic consistency is worse when

189

distinguishing between the intermediate categories (indefinite for dysplasia versus LG-D, and LG-D versus HG-D) [2,32]. Given this lack of concordance, the Crohn’s and Colitis Foundation of America consensus guidelines and the US Multisociety Task Force strongly recommend that dysplasia, as assessed prior of any surgical treatment, must be confirmed by a second, experienced gastrointestinal pathologist [49,80,81].

9. Diagnosing dysplasia in IBD 9.1. Gross (endoscopy) classification A peculiar feature of IBD-related dysplasia is its macroscopic variability [82]. Grossly, dysplasia is distinguished as flat or elevated, depending on whether or not it corresponds to an endoscopically visible lesion [61,83–87]. This distinction (while difficult) is important because it prompts different therapeutic strategies [85,88]. Flat dysplasia is often found in random biopsy specimens obtained from unremarkable mucosa, so its detection depends on how “aggressively” the mucosa is randomly sampled. Dysplasia assessed in endoscopically elevated/visible lesions has been termed DALM (dysplasia-associated lesion or mass) [83,89]. DALMs include (endoscopically not amendable) single and/or multiple polyps, bumps, plaques, velvety patches or nodules [83,90], and can easily remain hidden among the gross inflammatory abnormalities encountered in IBD (making their endoscopic detection a challenge even for experienced practitioners). More recently, the definitions of adenoma-like mass or dysplasia (ALM or ALD) have been proposed. ALM is applied to polypoid dysplasia with no adjacent flat component, endoscopically indistinguishable from a sporadic (sessile or pedunculated) polyp [91,92] and completely removable by endoscopy. Histology is of little help in differentiating DALM from ALM and this distinction basically relies on endoscopy [93].

9.2. Histological classification Dysplasia (synonyms: intraepithelial or non-invasive neoplasia) consists of unequivocally neoplastic epithelium confined to the basement membrane (no invasion of the lamina propria) [39]. It basically comprises two concurrent alterations, i.e. a disturbed architecture and cytological atypia [39,94]. Theoretically, similar criteria should be applied consistently to the assessment of dysplasia in both sporadic polyps (adenomas) and IBD, but this is only partially true because the architectural criterion prevails when dysplasia is graded as part of a sporadic adenoma, whereas both cytology and architecture are involved in the assessment/grading of IBD-associated dysplastic lesions (see below). Regardless of the endoscopic appearance of a lesion (i.e. raised or flat), the histological criteria for reporting dysplasia in IBD are basically the same [39,85,94]. The histological classification of dysplasia in IBD is based on Riddell et al.’s 1983 consensus report. In their seminal study, the Authors proposed classifying biopsy specimens in 5 categories: negative for dysplasia (which implies normal mucosa or mucosa with regenerative changes); indefinite for dysplasia; positive for low-grade dysplasia (LG-D); positive for high-grade dysplasia (HGD); or invasive cancer [39]. Although they recommended further dividing the indefinite category into probably negative, probably positive, unknown, many pathologists consider this unnecessary. It is generally accepted that Ca-CRC occurs through a progression from normal mucosa to LG-D, then HG-D, and finally cancer [10]. This classification is less reliable in detecting or predicting

190


CRC than might be expected, however, because LG-D can precede (or coexist with?) CRC without going through the HG-D phase. Dysplasia is a combination of architectural and cytological (nuclear and cytoplasmic) abnormalities. Its architectural features include a villiform surface and crypt budding, branching, and crowding (the latter commonly referred as a “back-to-back” growth pattern). The irregularity of the crypts’ contours and the presence of intraluminal bridges (“cribriforming”) are features of its architecture. The nuclear changes include hyperchromasia, nuclear pleomorphism (variability in size/shape), prominent nucleoli, a high nuclear-cytoplasm ratio, crowding, stratification, and excessive and/or atypical mitoses. The cytoplasm is mostly basophilic with little or no goblet cell mucin (a feature similar to the one seen in immature basal crypt epithelium). The colocyte maturation gradient (typical of nondysplastic crypts) is not seen in dysplastic epithelia, which are consistently monomorphic along the whole crypt axis. 9.2.1. Negative for dysplasia The term “negative for dysplasia” applies to epithelium that is regenerative in nature. In the presence of active inflammation (cryptitis, crypt abscesses, or ulceration), the epithelium can undergo marked reactive changes that may mimic some of the “atypical” features of dysplasia. Surface epithelial “maturation” is the most characteristic feature of non-dysplastic “regenerating” epithelium [37]. 9.2.2. Indefinite for dysplasia lesions In the setting of active inflammation/ulceration, regenerating epithelia may show atypia difficult to distinguish from true dysplasia: these features may be appropriately labelled as “indefinite for dysplasia”. In everyday diagnostic practice, this diagnostic category is most frequently applied when: (a) technical issues (sectioning or staining) interfere with the interpretation of cytological/architectural abnormalities; (b) in cases of severe atypia coexisting with inflammation/ulceration; (c) when dysplasia-like changes are only focal and/or restricted to the crypt bases. The prevalence of lesions judged to be indefinite for dysplasia is basically proportional to how much confidence the pathologist has with IBD, and that is why it is generally recommended that any potential diagnosis of dysplasia by submitted to the second opinion of an experienced IBD pathologist [38,49]. 9.2.3. Low-grade dysplasia (LG-D) In LG-D, crowded glands with mild size/shape abnormalities are basically similar to those seen in tubular adenomas. Dysplastic epithelium usually shows no surface maturation. Dysplastic cells have large cigar-shaped, basally orientated hyperchromatic nuclei (i.e. limited to the basal half of the cell cytoplasm, without full thickness stratification). The cytoplasm is mucin-depleted and hypereosinophilic. Mitotic figures may be prominent, but atypical mitotic figures are usually rare [37]. 9.2.4. High-grade dysplasia (HG-D) In HG-D, both architectural disruptions and cell atypia become prominent. Major abnormalities of the gland architecture (complex crypt budding, branching or a back-to-back growth pattern) are usually seen, possibly with cystic changes, a villiform surface, and cribriforming. Cells consistently feature a high nuclear/cytoplasm ratio, loss of nucleus polarity, and nuclear pleomorphism. Mitoses are increased and/or atypical (even at surface epithelium level). In some instances, high-grade nuclei are rounded, but nucleoli are always prominent and chromatin is “malignant” [95–97].

9.2.5. Low-grade versus high-grade dysplasia Histology should assess dysplasia according to its most atypical component, but even detailed descriptions do not prevent a significant inter-observer variability: even among GI pathologists, the subjective perception of “cell atypia”, “disturbed architecture”, and “cell differentiation” may result in inconsistent assessments. There is also controversy regarding the proportion of high-grade dysplastic crypts needed to upgrade a particular biopsy from lowto high-grade [39,82]. The IBD Dysplasia Morphology Study Group only suggests that a biopsy should not be considered high-grade “based solely on the presence of high-grade dysplasia in one or two crypts” [39], but fails to say how prevalent the high-grade changes have to be to indicate a case progressing from low- to high-grade. The histological assessment of LG-D versus HG-D thus remains subjective and the prognostic significance of the extent of dysplasia, be it low- or high-grade is consequently “unstable” (to some degree at least) [37]. 9.2.6. Intramucosal and invasive adenocarcinoma Carcinoma is defined as the true spreading of neoplastic cells beyond the basal membrane of the dysplastic crypts. Cancer cells invading the lamina propria or muscularis mucosa are defined as “intramucosal carcinoma”, whereas in “submucosal carcinoma”, cancer cells are unequivocally detected in the submucosal layer. The foci of early invasive carcinoma often consist of small glands, single neoplastic clusters, or isolated cancer cells. Infiltrating glands vary in size and shape, and may show intraluminal necrosis; periglandular desmoplasia is a reliable feature of invasive cancer and it is usually associated with an (at least) submucosal extension [37]. 10. Managing dysplasia 10.1. Indefinite for dysplasia lesions in flat mucosa Biopsies found indefinite for dysplasia should be reviewed by an expert GI pathologist and, if this classification is confirmed, a follow-up biopsy should be obtained within 3–6 months. 10.2. Low-grade dysplasia in flat mucosa Any biopsies reported as being “positive for LGD” should be confirmed by a second experienced gastrointestinal pathologist. Controversy exists as to the management of LGD because its natural history is unknown at this time. A patient confirmed as having multifocal flat LGD (2 or more biopsies with LGD from a single screening or surveillance examination) or repetitive flat LGD (2 or more examinations with at least one focus of LGD) should be strongly encouraged to undergo prophylactic total proctocolectomy. Recent evidence indicates that the 5-year rate of progression to HGD or CRC for patients with confirmed unifocal LGD (only 1 biopsy positive for LGD in a screening or surveillance examination) seems to be similar to that of multifocal LGD [98], so such patients should also be offered prophylactic proctocolectomy. Regardless of the focality of flat LGD, if a surgical strategy is deferred and patients elect to continue with surveillance, a repeat examination should be performed within 3–6 months after LGD was discovered. It should be stressed that, for patients with LGD opting for a non-operative strategy for, a subsequent negative examination is not enough to enable them to return to routine surveillance; they should continue to be examined more frequently. Again, an extensive biopsy protocol is recommended to ensure that the diagnosis is correct.


191

Fig. 2. Strategies of patient’s management according to both the gross (endoscopy) and the histology features.

10.3. High-grade dysplasia in flat mucosa As with LG-D, a finding of HG-D should be confirmed by an expert pathologist. If HG-D is confirmed, the high synchronous and metachronous adenocarcinoma rate means that total proctocolectomy is to be strongly recommended.

10.4. Dysplasia in raised lesions (DALM and ALM) The distinction between DALM and ALM is important because the former warrants colectomy, while the latter can be managed simply with polypectomy and surveillance [99]. The unfavourable clinical significance of DALM comes from the related high rates of synchronous cancers [83,90]. In 12 DALMbearing colons, Blackstone et al. reported 7 cancers (5/7 with only mild or moderate dysplasia in presurgical biopsies) [81]. A subsequent compilation of the results of ten surveillance programmes reported 17 cancers among 40 colectomies prompted by DALM [89]. It was concluded that DALM is an indication for colectomy irrespective of the grade of dysplasia in the patient’s preoperative biopsies. Unlike DALM, ALM can be managed safely with polypectomy, taking biopsies of the surrounding flat mucosa [100]. A study from the Mount Sinai Hospital in New York reported that a conservative management of 48 UC patients with a total of 70 such polyps (3 of them with high-grade dysplasia) did not result in any adverse outcomes during a mean follow-up period of 4.1 years [57]. Similar conclusions were reached in a concurrent study [92], and were further confirmed after a longer follow-up [100]. It is important to realize that the burden of deciding whether or not a polyp qualifies as adenoma-like rests with the endoscopist: unfortunately, a recent paper from Farraye et al. showed that even experts have great difficulty in differentiating between the abovementioned categories [101]. Recently, Srivastava et al. [102] described multiple hyperplastic and serrated colon lesions as assessed in 3 IBD patients with long standing disease. The similarity between such a clinicopathological features and the hyperplastic/serrated polyposis

syndrome, would suggest a closer surveillance of any patient with similar situations.

11. Dysplasia in the natural history of CRC Once dysplasia has been diagnosed, its management relies on an understanding of its natural history (Fig. 2). In 1949, Warren and Sommers first suggested that UC-associated dysplasia was a cancer precursor [103]. Since then, a growing body of evidence has unequivocally demonstrated that dysplasia is not only a precursor, but also a marker of co-existing CRC [104]. Carcinogenesis in IBD does not always follow a sequential progression from LG-D to HG-D, and eventually to cancer [2]. Ullman et al. [98] showed that cancer can arise in patients with no prior dysplasia, or without first progressing from LGD to HGD. CRC arising in IBD is often multifocal and more aggressive than the sporadic variant [82,105,106]. Of course, sporadic cancer (unrelated to their IBD) may occur coincidentally in IBD patients too [85,94].

11.1. Flat low-grade dysplasia In 16–54% of patients, flat LG-D progresses to more advanced lesions (HGD or CRC) over a 5-year follow-up [17,76,97,45,107–109]. Among series of flat LG-D patients who underwent urgent colectomy, the prevalence of coexisting HG-D/CRC was in the range of 16–34%; these patients’ surgical specimens revealed much more advanced disease than had been apparent in their biopsies [17,28,89,98]. In the latest meta-analysis, flat LG-D was found associated with a 9-fold risk of developing CRC (OR: 9.0, 95%CI: 4.0–20.5) and a 12fold risk of developing advanced neoplasia (HDG or CRC) (OR: 11.9, 95%CI: 5.2–27) by comparison with IBD patients with no dysplasia. The positive predictive value of flat LG-D for the risk of CRC was 22% [110].

192


It is also worth noting that, according to one study, monofocal LG-D was just as likely as multifocal LG-D to progress to HG-D or cancer [98].

Grants We would like to acknowledge the continuous support of AIRC (Associazione Italiana per la Ricerca sul Cancro).

11.2. Flat high-grade dysplasia Acknowledgments In systematic reviews, CRC was found on colectomy specimens in 42–67% of patients operated immediately for flat HG-D [17,89,111]. In Bernstein’s experience, 32% of patients found to have flat HG-D after initial colonoscopy subsequently developed cancer [89].

The authors are in debt with professor Karel Geboes who inspired the present manuscript during his teaching activity at the Department of Pathology of Padova University in November 2011. References

11.3. Raised dysplasia In Bernstein et al.’s review of ten prospective studies, 43% of patients who had colectomy for DALM had coexisting CRC (regardless of the grade of dysplasia in the DALM) [84]. Other Authors reported rates of coexisting CRC ranging from 31% to 65% in cases of DALM [17,111]. 11.4. Indefinite for dysplasia The clinico-pathological behaviour of lesions “indefinite for dysplasia” has been poorly addressed. Bernstein’s review found that 28% of such cases progressed to HG-D and 9% to cancer [89]. In a 5-year follow-up study on 56 patients enrolled with “indefinite” lesions, 9% progressed to HG-D or CRC; the progression rate was midway between the rates for patients with no dysplasia and those with LG-D [112]. 11.5. No dysplasia IBD patients with no dysplasia have the lowest rates of cancer progression. In Bernstein’s review, these subjects carried a less than 2.5% risk of developing HG-D or cancer [89]. Among 311 non-dysplastic UC patients followed up for 5 years, Ullman et al. reported a 1.1% incidence of CRC [112], while Lim et al. found that 4% of UC patients with no dysplasia developed HG-D or CRC after 10 years of follow-up [79]. 12. Conclusions The clinico-pathological link between IBD and CRC is well established and provides the rationale for (differentiated) endoscopic surveillance of patients with (long-standing) IBD without dysplasia, lesions indefinite for dysplasia, or low-grade dysplasia (and patients with late-onset IBD should be considered “more prone” to cancer development). In HG-D, colectomy should be considered the primary option. When LG-D is encountered within DALM, the cancer risk is higher than in corresponding non-DALM lesions and patients should be managed accordingly. Latest-generation endoscopic instruments do improve the quality of endoscopy, the reliability of neoplasia detection, and the consistency of biopsy sampling (though more sophisticated procedures, such as CLE, are more appropriate for research than for clinical purposes). Histology in expert hands remains the most reliable way to identify cancerprone cases (dysplasia patients); when histological findings suggest the need for surgery, a second opinion is mandatory. A centralized patient management (which broadens a physician’s experience) and educational strategies (to improve patients’ awareness) may help to optimize treatments and follow-up measures, both of which can help to reduce the IBD-associated cancer risk [113,114]. Conflict of interest No conflict of interest to declare.

[1] Crohn B, Rosenberg H. The sigmoidoscopic picture of chronic ulcerative colitis (non-specific). American Journal of the Medical Sciences 1925;170:220–8. [2] Itzkowitz SH, Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology 2004;126:1634–48. [3] Vagefi PA, Longo WE. Colorectal cancer in patients with inflammatory bowel disease. Clinical Colorectal Cancer 2005;4:313–9. [4] Devroede GJ, Taylor WF, Sauer WG, et al. Cancer risk and life expectancy of children with ulcerative colitis. New England Journal of Medicine 1971;285:17–21. [5] Winther KV, Jess T, Langholz E, et al. Longterm risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County. Clinical Gastroenterology and Hepatology 2004;2:1088–95. [6] Askling J, Dickman PW, Karlen P, et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology 2001;120:1356–62. [7] Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126:451–9. [8] Mathy C, Schneider K, Chen YY, et al. Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis. Inflammatory Bowel Diseases 2003;9:351–5. [9] Gupta RB, Harpaz N, Itzkowitz S, et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 2007;133:1099–105. [10] Itzkowitz SH, Yio X. Inflammation and cancer. Colorectal cancer in inflammatory bowel disease: the role of inflammation. American Journal of Physiology – Gastrointestinal and Liver Physiology 2004;287:G7–17. [11] Rubin DT, LoSavio A, Yadron N, et al. Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clinical Gastroenterology and Hepatology 2006;4:1346–50. [12] Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48:526–35. [13] Bernstein CN, Blanchard JF, Kliewer E, et al. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91:854–62. [14] Lakatos L, Mester G, Erdelyi Z, et al. Risk factors for ulcerative colitisassociated colorectal cancer in a Hungarian cohort of patients with ulcerative colitis: results of a population-based study. Inflammatory Bowel Diseases 2006;12:205–11. [15] Jess T, Loftus Jr EV, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted County, Minnesota. Gastroenterology 2006;130:1039–46. [16] Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 2003;18(Suppl. 2):1–5. [17] Rutter MD, Saunders BP, Wilkinson KH, et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006;130:1030–8. [18] Jess T, Rungoe C, Peyrin-Biroulet L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clinical Gastroenterology and Hepatology 2012 Jan 27 [Epub ahead of print]. [19] Ekbom A, Helmick C, Zack M, et al. Increased risk of large-bowel cancer in Crohn’s disease with colonic involvement. Lancet 1990;336:357–9. [20] Jess T, Winther KV, Munkholm P, et al. Intestinal and extra-intestinal cancer in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark. Alimentary Pharmacology and Therapeutics 2004;19:287–93. [21] Jess T, Gamborg M, Matzen P, et al. Increased risk of intestinal cancer in Crohn’s disease: a meta-analysis of population-based cohort studies. American Journal of Gastroenterology 2005;100:2724–9. [22] Gyde SN, Prior P, Macartney JC, et al. Malignancy in Crohn’s disease. Gut 1980;21:1024–9. [23] Greenstein AJ, Sachar DB, Smith H, et al. A comparison of cancer risk in Crohn’s disease and ulcerative colitis. Cancer 1981;48:2742–5. [24] Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn’s disease. Alimentary Pharmacology and Therapeutics 2006;23:1097–104. [25] Basseri RJ, Basseri B, Vassilaki ME, et al. Colorectal cancer screening and surveillance in Crohn’s colitis. Journal of Crohn’s and Colitis 2012 Feb [Epub ahead of print].

C. Mescoli et al. / Digestive and Liver Disease 45 (2013) 186–194 [26] Gillen CD, Walmsley RS, Prior P, et al. Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 1994;35:1590–2. [27] Soetikno RM, Lin OS, Heidenreich PA, et al. Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointestinal Endoscopy 2002;56:48–54. [28] Taylor BA, Pemberton JH, Carpenter HA, et al. Dysplasia in chronic ulcerative colitis: implications for colonoscopic surveillance. Diseases of the Colon and Rectum 1992;32:950–6. [29] Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic Crohn’s colitis. Gastroenterology 2001;120:820–6. [30] Webb BW, Petras RE, Bozdech JM, et al. Carcinoma and dysplasia in mucosal ulcerative colitis: a clinicopathologic study of 44 patients. American Journal of Clinical Pathology 1991;96:403–7. [31] Connell WR, Talbot IC, Harpaz N, et al. Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis. Gut 1994;35:1419–23. [32] Xie J, Itzkowitz SH. Cancer in inflammatory bowel disease. World Journal of Gastroenterology 2008;14:378–89. [33] Yashiro M, Carethers JM, Laghi L, et al. Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. Cancer Research 2001;61:2676–83. [34] Issa JP, Ahuja N, Toyota M, et al. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Research 2001;61:3573–7. [35] Svrcek M, El-Bchiri J, Chalastanis A, et al. Specific clinical and biological features characterize inflammatory bowel disease associated colorectal cancers showing microsatellite instability. Journal of Clinical Oncology 2007;25:4231–8. [36] Tahara T, Inoue N, Hisamatsu T, et al. Clinical significance of microsatellite instability in the inflamed mucosa for the prediction of colonic neoplasms in patients with ulcerative colitis. Journal of Gastroenterology and Hepatology 2005;20:710–5. [37] Odze RD. Pathology of dysplasia and cancer in inflammatory bowel disease. Gastroenterology Clinics of North America 2006;35:533–52. [38] Ullman TA. Dysplasia and colorectal cancer in Crohn’s disease. Journal of Clinical Gastroenterology 2003;36:S75–8. [39] Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Human Pathology 1983;14:931–68. [40] Judge TA, Lewis JD, Lichtenstein GR. Colonic dysplasia and cancer in inflammatory bowel disease. Gastrointestinal Endoscopy Clinics of North America 2002;12:495–523. [41] Collins PD, Mpofu C, Watson AJ, et al. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database of Systematic Reviews 2006;CD000279. [42] Harpaz N. Neoplastic precursor lesions related to the development of cancer in inflammatory bowel disease. Gastroenterology Clinics of North America 2007;36:901–26. [43] Zisman TL, Rubin DT. Colorectal cancer and dysplasia in inflammatory bowel disease. World Journal of Gastroenterology 2008;14:2662–9. [44] Lakatos PL, Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World Journal of Gastroenterology 2008;14:3937–47. [45] Ullman T, Odze R, Farraye FA. Diagnosis and management of dysplasia in patients with ulcerative colitis and Crohn’s disease of the colon. Inflammatory Bowel Diseases 2009;15:630–8. [46] Itzkowitz SH. Cancer prevention in patients with inflammatory bowel disease. Gastroenterology Clinics of North America 2002;31:1133–44. [47] Rubin DT, Kavitt RT. Surveillance for cancer and dysplasia in inflammatory bowel disease. Gastroenterology Clinics of North America 2006;35:581–604. [48] Mitchell PJ, Salmo E, Haboubi NY. Inflammatory bowel disease: the problems of dysplasia and surveillance. Techniques in Coloproctology 2007;11:299–309. [49] Itzkowitz SH, Present DH, Odze RD, et al. Crohn’s and Colitis Foundation of America Colon Cancer in IBD Study *Group. Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease. Inflammatory Bowel Diseases 2005;11:314–21. [50] Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. American Journal of Gastroenterology 2004;99:1371–85. [51] Carter MJ, Lobo AJ, Travis SP. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004;53(Suppl. 5):V1–16. [52] Eaden JA, Mayberry JF. Guidelines for the screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease. Gut 2002;51:10–2. [53] Lutgens MW, Vleggaar FP, Schipper ME, et al. High frequency of early colorectal cancer in inflammatory bowel disease. Gut 2008;57:1246–51. [54] Brackmann S, Andersen SN, Aamodt G, et al. Relationship between clinical parameters and the colitis-colorectal cancer interval in a cohort of patients with colorectal cancer in inflammatory bowel disease. Scandinavian Journal of Gastroenterology 2009;44:46–55. [55] Karvellas CJ, Fedorak RN, Hanson J, et al. Increased risk of colorectal cancer in ulcerative colitis patients diagnosed after 40 years of age. Canadian Journal of Gastroenterology 2007;21:443–6. [56] Sugita A, Sachar DB, Bodian C, et al. Colorectal cancer in ulcerative colitis. Influence of anatomical extent and age at onset on colitis-cancer interval. Gut 1991;32:167–9.

193

[57] Gyde SN, Prior P, Allan RN, et al. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres. Gut 1988;29:206–17. [58] Rubin CE, Haggitt RC, Burmer GC, et al. DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 1992;103:1611–20. [59] Woolrich AJ, DaSilva MD, Korelitz BI. Surveillance in the routine management of ulcerative colitis: the predictive value of low-grade dysplasia. Gastroenterology 1992;103:431–8. [60] Kaltz B, Bokemeyer B, Hoffmann J, et al. Surveillance colonoscopy in ulcerative colitis patients in Germany (in German). Zeitschrift fur Gastroenterologie 2007;45:325–31. [61] Rutter MD, Saunders BP, Wilkinson KH, et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointestinal Endoscopy 2004;60:334–9. [62] Rubin DT, Rothe JA, Hetzel JT, et al. Are dysplasia and colorectal cancer endoscopically visible in patients with ulcerative colitis? Gastrointestinal Endoscopy 2007;65:998–1004. [63] Blonski W, Kundu R, Lewis J, et al. Is dysplasia visible during surveillance colonoscopy in patients with ulcerative colitis? Scandinavian Journal of Gastroenterology 2008;43:698–703. [64] Sada M, Igarashi M, Yoshizawa S, et al. Dye spraying and magnifying endoscopy for dysplasia and cancer surveillance in ulcerative colitis. Diseases of the Colon and Rectum 2004;47:1816–23. [65] Rutter MD, Saunders BP, Schofield G, et al. Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 2004;53:256–60. [66] Marion JF, Waye JD, Present DH, et al. Chromoendoscopy Study *Group at Mount Sinai School of Medicine. Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial. American Journal of Gastroenterology 2008;103:2342–9. [67] Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004;53:1813–6. [68] Kiesslich R, Fritsch J, Holtmann M, et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003;124:880–8. [69] Hurlstone DP, Sanders DS, Lobo AJ, et al. Indigo carmine-assisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy 2005;37:1186–92. [70] Buda A, Lamboglia F, Hatem G, et al. Evolving endoscopic technologies for the detection of dysplasia in inflammatory bowel diseases. Annali Italiani di Chirurgia 2011;82:29–35. [71] Neumann H, Vieth M, Atreya R, et al. Prospective evaluation of the learning curve of confocal laser endomicroscopy in patients with IBD. Histology and Histopathology 2011;26:867–72. [72] Moussata D, Goetz M, Gloeckner A, et al. Confocal laser endomicroscopy is a new imaging modality for recognition of intramucosal bacteria in inflammatory bowel disease in vivo. Gut 2011;60:26–33. [73] Odze RD, Goldblum J, Noffsinger A, et al. Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology. Modern Pathology 2002;15:379–86. [74] Eaden J, Abrams K, McKay H, et al. Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. Journal of Pathology 2001;194:152–7. [75] Dixon MF, Brown LJ, Gilmour HM, et al. Observer variation in the assessment of dysplasia in ulcerative colitis. Histopathology 1988;13:385–97. [76] Connell WR, Lennard-Jones JE, Williams CB, et al. Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis. Gastroenterology 1994;107:934–44. [77] Riddell RH. Grading of dysplasia. European Journal of Cancer 1995;31A:1169–70. [78] Melville DM, Jass JR, Morson BC, et al. Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome. Human Pathology 1989;20:1008–14. [79] Lim CH, Dixon MF, Vail A, et al. Ten-year follow-up of ulcerative colitis patients with and without low grade dysplasia. Gut 2003;52:1127–32. [80] Greenson JK. Dysplasia in inflammatory bowel disease. Seminars in Diagnostic Pathology 2002;19:31–7. [81] Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale – update based on new evidence. Gastroenterology 2003;124:544–60. [82] Harpaz N, Talbot IC. Colorectal cancer in idiopathic inflammatory bowel disease. Seminars in Diagnostic Pathology 1996;13:339–57. [83] Blackstone MO, Riddell RH, Rogers BGH, et al. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 1981;80:366–74. [84] Itzkowitz S, Ullman T. The world isn’t flat. Gastroendoscopy 2004;60:426–7. [85] Odze RD. Adenomas and adenoma-like DALMs in chronic ulcerative colitis: a clinical, pathological, and molecular review. American Journal of Gastroenterology 1999;94:1746–50. [86] Rutter M, Bernstein C, Matsumoto T, et al. Endoscopic appearance of dysplasia in ulcerative colitis and the role of staining. Endoscopy 2004;36:1109–14. [87] Ahmadi A, Polyak S, Draganov PV. Colorectal cancer surveillance in inflammatory bowel disease: the search continues. World Journal of Gastroenterology 2009;15:61–6.

194


[88] Odze RD. Recent advances in inflammatory bowel disease. Modern Pathology 2003;16:347–58. [89] Bernstein CN, Shanahan F, Weinstein WM. Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis? Lancet 1994;343:71–4. [90] Butt JH, Konishi F, Morson DM, et al. Macroscopic lesions in dysplasia in carcinoma complicating ulcerative colitis. Digestive Diseases and Sciences 1983;28:18–26. [91] Rubin PH, Friedman S, Harpaz N, et al. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology 1999;117:1295–300. [92] Englesjerd M, Farraye FA, Odze RD. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis. Gastroenterology 1999;117:1288–94. [93] Schneider A, Stolte M. Differential diagnosis of adenomas and dysplastic lesions in patients with ulcerative colitis. Zeitschrift fur Gastroenterologie 1993;31:653–6. [94] Torres C, Antonioli D, Odze RD, et al. Polypoid dysplasia and adenomas in inflammatory bowel disease. American Journal of Surgical Pathology 1998;22:275–84. [95] Rubio CA, Johansson P, Slezak U, et al. Villous dysplasia. An ominous histologic sign in colitic patients. Diseases of the Colon and Rectum 1984;27:283–7. [96] Anderson SN, Lovig T, Clausen OPF, et al. Villous, hypermucinous mucosa in long-standing ulcerative colitis shows high frequency of K-ras mutation. Gut 1999;45:686–92. [97] Rubio CA, Befrits R, Jaramillo E, et al. Villous and serrated adenomatous growth bordering carcinomas in inflammatory bowel disease. Anticancer Research 2000;20:4761–2. [98] Ullman T, Croog V, Harpaz N, et al. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 2003;125:1311–9. [99] Ludeman L, Shephard NA. Problem areas in the pathology of chronic inflammatory bowel disease. Current Diagnostic Pathology 2006;12:248–60. [100] Odze RD, Farraye FA, Hecht JL, et al. Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis. Clinical Gastroenterology and Hepatology 2004;2:534–41. [101] Farraye FA, Waye JD, Moscandrew M, et al. Variability in the diagnosis and management of adenoma-like and non-adenoma-like dysplasia-associated lesions or masses in inflammatory bowel disease: an Internet-based study. Gastrointestinal Endoscopy 2007;66:519–29.

[102] Srivastava A, Redston M, Farraye FA, et al. Hyperplastic/serrated polyposis in inflammatory bowel disease: a case series of a previously undescribed entity. American Journal of Surgical Pathology 2008;32:296–303. [103] Warren S, Sommers SC. Pathogenesis of ulcerative colitis. American Journal of Pathology 1949;25:657–79. [104] Bernstein CN. Natural history and management of flat and polypoid dysplasia in inflammatory bowel disease. Gastroenterology Clinics of North America 2006;35:573–9. [105] Greenstein AJ, Slater G, Heimann TM, et al. A comparison of multiple synchronous colorectal cancer in ulcerative colitis, familial polyposis coli, and de novo cancer. Annals of Surgery 1986;203:123–8. [106] Delaunoit T, Limburg PJ, Goldberg RM, et al. Colorectal cancer prognosis among patients with inflammatory bowel disease. Clinical Gastroenterology and Hepatology 2006;4:335–42. [107] Linberg B, Perrson B, Veress B, et al. Twenty years’ colonoscopic surveillance of patients with ulcerative colitis. Detection of dysplastic and malignant transformation. Scandinavian Journal of Gastroenterology 1996;31:1195–204. [108] Eaden J. Review article: colorectal carcinoma and inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 2004;20(Suppl. 4): 24–30. [109] Ullman TA, Loftus Jr EV, Kakar S, et al. The fate of low-grade dysplasia in ulcerative colitis. American Journal of Gastroenterology 2002;97: 922–7. [110] Thomas T, Abrams KA, Robinson RJ, et al. Meta-analysis: cancer risk of lowgrade dysplasia in chronic ulcerative colitis. Alimentary Pharmacology and Therapeutics 2007;25:657–68. [111] Collins RH, Feldman M, Fordman JS. Colon cancer, dysplasia, and surveillance in patients with ulcerative colitis: a critical review. New England Journal of Medicine 1987;316:1654–8. [112] Ullman TA, Croog V, Harpaz N, et al. Progression to colorectal neoplasia in ulcerative colitis: effect of 5-aminosalicylic acid. Clinical Gastroenterology and Hepatology 2008;6:1225–30. [113] Mooiweer E, Baars JE, Lutgens MW, et al. Disease severity does not affect the interval between IBD diagnosis and the development of CRC: results from two large, Dutch case series. The Journal of Crohn’s and Colitis 2012;6: 435–40. [114] Angelucci E, Orlando A, Ardizzone S, et al. Internet use among inflammatory bowel disease patients: an Italian multicenter survey. European Journal of Gastroenterology and Hepatology 2009;21:1036–41.