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Inflammatory bowel disease-related dysplasia: evolving diagnostic and therapeutic paradigms
MINI-SYMPOSIUM: PRECURSOR LESIONS OF GASTROINTESTINAL EPITHELIAL NEOPLASMS
Inflammatory bowel diseaserelated dysplasia: evolving diagnostic and therapeutic paradigms
however increasing evidence that targeted biopsies of lesions identified on a high-resolution endoscope represents a more efficient means of detecting dysplasia, and random biopsies do not increase the yield of neoplasia.7,8
Stratification of risk in IBD The degree of cancer risk is modulated by several factors including the extent of colitis, duration of disease, the presence of primary sclerosing cholangitis, and the severity of inflammation: these features assist in stratifying risk and guide the management of patients. Patients with pancolitis and primary sclerosing cholangitis are at the highest risk of malignancy, while patients with isolated proctitis are at no additional risk of cancer. Thus, patients with proctitis do not require cancer surveillance while those with primary sclerosing cholangitis and pancolitis are placed on an accelerated screening protocol. The severity of microscopic inflammation over time has also been shown to be an independent risk factor for colorectal neoplasia among patients with ulcerative colitis.9
Vikram Deshpande
Abstract Patients with inflammatory bowel disease show an excess colon cancer incidence and mortality. Colonoscopy with biopsies represents the most robust strategy for decreasing the risk of malignancy. Targeted biopsies of lesions identified on a high-resolution endoscope and chromoendoscopy is now believed to be a more efficient means of detecting dysplasia, and random biopsies do not increase the yield of neoplasia. In clinical practice, the diagnosis of dysplasia is based on a constellation of changes that include cytologic, architectural and maturational abnormalities. Morphologically, most dysplasia is of the adenomatous type. The distinction of low-grade dysplasia from reactive epithelial changes remains a significant and sometime an insurmountable problem. Although p53 immunohistochemistry has been proposed as a biomarker for dysplasia, positive staining reactive conditions significantly limits its utility as a marker of dysplasia. The advent of high resolution endoscopes and chromoendoscopy allows for the visualization of the vast majority of dysplastic lesions, leaving only a minority of lesions are endoscopically invisible. Advances in screening and endoscopic resection techniques now permit conservative management of endoscopically visible dysplastic lesion, including some cases of high-grade dysplasia.
Diagnosis of dysplasia Endoscopic appearance Endoscopically the appearance is highly variable and includes nodules, plaque-like lesions, a filiform appearance, as well as stricture formation (Figure 1a and b). Histology Colonic biopsies are grouped into five categories: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, highgrade dysplasia and invasive carcinoma. A revised Vienna classification is used in many centers in Europe.10 The classification and criteria for dysplasia in inflammatory bowel disease were proposed by Riddell and colleagues in 1983.11 Intra- and inter-observer variability in the interpretation of biopsy specimens for dysplasia in inflammatory bowel disease is well documented, even among experienced gastrointestinal pathologists.12,13 In general, levels of agreement are highest for the category of high-grade dysplasia and for biopsy specimens considered negative for dysplasia, but are lowest at the lower end of the spectrum (e.g., indefinite for dysplasia versus low-grade dysplasia).
Keywords dysplasia; inflammatory bowel disease; p53
Introduction While the increased risk of cancer in patients with inflammatory bowel disease is widely acknowledged, over the last decade its become increasingly apparent that the extent of the risk may have been over-estimated, a consequence of the bias introduced by the study of referral center cohorts. A recent Danish population based study found no excess risk of cancer in ulcerative colitis.1 This may well be a consequence of better surveillance, more robust control of inflammation, as well as use of agents such as 5-aminosalicylates, a potentially chemopreventive agent. On the other hand, a recent study from Northern California found excess colon cancer incidence and mortality in patients with inflammatory bowel disease.2 Regular colonoscopy with biopsies represents the most robust strategy for decreasing the risk of malignancy.3e6 Until recently, multiple random biopsies from diseased/previously diseased colon was the standard of care. There is
Defining dysplasia Dysplasia, also referred to as intraepithelial neoplasia, is a preneoplastic lesion that puts the patient at a high risk of invasive carcinoma, both at the site of biopsy and other sites within the diseased organ. Dysplasia is defined as unequivocally neoplastic epithelium confined to the basement membrane. This definition has little practical value since evaluating the basement membrane and defining ‘unequivocally neoplastic’ represent significant and sometimes insurmountable challenges. In clinical practice the diagnosis of dysplasia is based on a constellation of changes that include cytologic, architectural and maturational abnormalities. Cytologically, dysplastic cells are characterized by nuclear stratification, cellular crowding, as well as hyperchromatic and enlarged nuclei (Figures 2 and 3). Common architectural abnormalities include small glandular profiles, irregularly shaped glands, glandular crowding, crypt budding
Vikram Deshpande MD Associate Pathologist, Department of Pathology, Massachusetts General Hospital and Associate Professor of Pathology, Harvard Medical School, Boston, MA, USA. Conflicts of interest: none declared.
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Figure 1 (a and b) Endoscopically visible dysplasia arising in inflammatory bowel disease (arrows).
and cribriforming, the presence of back-to-back glands with varying degrees of stromal extinction, and a villiform surface (Figures 4 and 5). It should be noted that severe architectural changes are typically seen only in high-grade dysplasia. The lack of maturation represents a key feature that distinguishes a reactive process (also see below) from dysplasia. Within normal colonic epithelium, proliferation is confined to the crypt base. It is notable that stem cells are identified at the bottom of the crypt and proliferative activity is noted immediately above this region e thus Ki67 positive cells are confined to the bottom 1/3rd of the crypt. This contrasts with the location of stem cells and the proliferative zone in the stomach e situated in the higher regions of the mucosa. The colonic cells above the crypt base show progressively smaller nuclei and differentiate
into goblet cells, absorptive and endocrine cells. This pattern of acquisition of terminally differentiated cells is often referred to as maturation. Dysplastic epithelium often lacks maturation, instead ‘proliferative-type’ epithelium is identified within the upper 1/3rd of the crypts, and more significantly, on the surface epithelium. While lack of maturation distinguishes dysplasia from reactive epithelium, it should be noted that the expanded proliferative zone may extend into the upper half of the crypt in regenerative states (Figure 6). Furthermore, it should be recognized that the length of the crypts may be significantly reduced in cases with marked regenerative changes e as is often found adjacent to an ulcer. In this scenario the proliferative zone may extend extremely close to the surface epithelium, as a result only subtle (or rarely none) evidence of maturation may be evident
Figure 2 Ulcerative colitis with low-grade dysplasia. The image shows lack of maturation. However, the polarity of the cells is preserved (a). Immunohistochemistry performed on this case show strong reactivity for p53. The reactivity extends to the upper half of the crypts (b).
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adenomas i.e. show an adenomatous appearance, and are thus readily diagnosed as dysplasia. However, regenerative epithelium may show enlarged hyperchromatic nuclei with stratification, a high nuclear to cytoplasmic ratio, and resemble tubular adenomas and dysplasia. Broadly speaking, there two reason for uncertainty and a diagnosis of indefinite for dysplasia: (1) severe inflammation/ ulceration, (2) technical reasons e a tangential cut, lack of surface epithelium, poor orientation, poor fixation, and cautery artifacts. An extremely helpful feature in making this distinction is the abrupt demarcation between dysplastic and benign epithelium. The atypia in regenerative epithelium merges gradually with adjacent normal epithelial cells. It is unwise to render a diagnosis of dysplasia in the presence of an ulcer, unless there is unequivocal evidence of high-grade dysplasia or carcinoma. It should be noted that the erosion/ulcer may not be included in the biopsy, and thus other evidence should be sought such as the presence fibrinopurulent exudate or granulation tissue. The presence of intraepithelial/intramucosal neutrophils do not exclude a diagnosis of dysplasia. The potential for regenerative epithelial changes to mimic dysplasia was highlighted in a recent study of ischaemic enterocolitis.15 Based on cytologic criteria alone these authors were unable to distinguish dysplasia from regenerative mucosa. Interestingly, neither p53 (also see below) nor Ki67 could assist in this distinction, bringing into question the utility of these markers in the diagnosis of dysplasia.15 A helpful rule of thumb is to avoid evaluating the atypical epithelium in isolation; instead it is prudent to judge the epithelium by the company it keeps.
Figure 3 Ulcerative colitis with dysplasia. The adenomatous appearance as well as the lack of maturation is obvious. The focal loss of polarity of the surface epithelial cells (on the right side of the image) is suggestive of high-grade dysplasia.
(Figure 6). This accounts for the reluctance of pathologists to render an unequivocal diagnosis of dysplasia on biopsies obtained immediately adjacent to an ulcer. The convention that a diagnosis of dysplasia requires the involvement of the surface by neoplastic epithelium has been challenged e the so-called basal crypt dysplasia.14 However, the concept of colonic basal crypt dysplasia is generally not accepted. Nevertheless, if significant atypia is identified in the basal crypt region, every effort should be made to identify surface involvement, and this generally involves requesting additional levels.
Distinction of low-grade from high-grade dysplasia This is one of the more vexing problems associated with the diagnosis of dysplasia in inflammatory bowel disease. The distinction is central to many key management decisions e a diagnosis of high-grade dysplasia may trigger total colectomy, while the diagnosis of low-grade dysplasia may require only accelerated surveillance. Unfortunately, there is no single feature that distinguishes low-grade from high-grade dysplasia,
Distinction of reactive from dysplastic epithelium and the indefinite for dysplasia category The term ‘indefinite for dysplasia’ is not a diagnostic category, but simply a placeholder with the understanding that subsequent biopsies will provide unequivocal evidence of dysplasia or lack thereof. Fortunately, unlike the upper gastrointestinal tract, the majority of dysplastic lesions resemble sporadic tubular
Figure 4 Ulcerative colitis with high-grade dysplasia. The marked architectural abnormalities suggest high-grade dysplasia e glandular crowding, budding and stromal extinction (a). High power view show cells with vesicular nuclei and prominent nucleoli. However, the polarity is largely intact (b).
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Figure 5 Colitis with high-grade dysplasia (a and b). Some of the glands display a serrated profile.
the distinction requires evaluation of a constellation of features. The architectural alterations are more severe in highgrade dysplasia e changes such as crypt crowding, budding and irregularly shaped crypts are indicative of high-grade dysplasia (see Figure 4). Another useful criterion is the presence of full thickness nuclear stratification in high-grade dysplasia: nuclei of low-grade dysplasia they are generally confined to the base of the epithelium, while with high-grade dysplasia are haphazardly distributed in both the basal as well as the apical regions of the epithelium. The nuclei in lowgrade dysplasia tend to be penicillate, while in high-grade dysplasia the cells appear more “undifferentiated” with round to oval nuclei, coarse chromatin, and enlarged nucleoli (see
Figure 4). Loss of polarity is another key feature of high-grade dysplasia. Normal columnar cells and their nuclei are placed perpendicular to the basement membrane. The loss of this characteristic relationship between the cells and the basement membrane constitutes loss of polarity. The presence of atypical mitoses extending to the surface is yet another feature of highgrade dysplasia. The quantitative aspects of this distinction have not been addressed, although it is often stated (with little corroborative evidence) that a diagnosis of high-grade dysplasia requires at least 2 crypts showing unequivocal changes of high-grade dysplasia. It should be noted that the changes of Crohn’s related-dysplasia seen in Crohn’s disease are generally similar to that seen in ulcerative colitis.
Figure 6 Ulcerative colitis with reactive epithelial changes. The epithelium immediately adjacent to the ulcer is similar to an adenoma (a). Focally, the adenomatous epithelium appears to extend to the surface epithelium (b). Incomplete maturation is seen (arrow). The basal glands e the proliferative region of the mucosa e is indistinguishable from an adenoma (c).
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Figure 7 Low-grade tubuloglandular adenocarcinoma. Note the well formed glandular structures infiltrating into the submucosa (a). Invasive glands in the submucosa (b).
Other less common forms of dysplasia The epithelium of hypermucinous dysplasia may show small banal appearing basally placed nuclei with abundant apical mucin, often in a papillary configuration, an appearance that could easily be dismissed as reactive.16 Fortunately, this is typically a focal finding, and foci of adenomatous dysplasia are invariably found elsewhere in the biopsy. The presence of mucinous epithelium, particularly if villiform in contour, is suggestive of dysplasia. Pure hypermucinous dysplasia is rare. The natural history of pure hypermucinous dysplasia is unknown. Whether serrated colonic mucosa lacking cellular atypia i.e. conventional dysplasia increases the risk of malignancy remains uncertain.17 These changes are referred to as serrated epithelial changes, an attempt to distinguish this lesion from sessile serrated adenoma and traditional serrated adenoma. Nevertheless, given the concern that serrated epithelial changes may increase the risk of colon carcinoma, it appears prudent for pathologist to document this finding.17
became the standard of care for these patients. However, this paradigm did not take into account sporadic adenomas in patients with inflammatory bowel disease. Mistaking a sporadic adenoma for the more ominous DALM would inadvertently subject the patient to a total colectomy. These sporadic adenomas were subsequently designated as adenoma-like lesions, and the patients were treated conservatively.19e21 Lesions that appeared invisible to the endoscopist were designated as flat dysplasia, and until recently the standard of care for ‘flat’ highgrade dysplasia was total colectomy. Given the clinical significance of this distinction, numerous attempts were made to uncover histologic differences between DALMs and sporadic adenomas. In one study DALMs were more frequently associated with tubulovillous or villous architecture, an admixture of normal and dysplastic epithelium at the surface of the polyps, and increased lamina propria mononuclear inflammation.22 Dysplasia in the adjacent ‘flat’ mucosa also favoured DALM, as did the combination of strong p53 expression and absent or weak beta-catenin expression. However, these criteria were neither robust nor objective, and thus were seldom used in clinical practice. Instead, the onus for this distinction lay with the endoscopist: adenoma-like dysplastic lesions are wellcircumscribed, smooth or papillary, sessile or pedunculated polyps while DALMs could be velvety patches, plaques, nodules, mucosal thickenings, stricturing lesions, and broad-based masses. A paradigm shift to the therapeutic algorithm has been spurred by the availability of high-resolution white-light endoscopes as well as newer endoscopic techniques, particularly chromoendoscopy, the latter now considered standard of care when screening for malignancy in inflammatory bowel disease. Accordingly, lesions that might have been invisible in the past are both readily visualized and the borders defined, permitting endoscopic resection. This paradigm shift has also necessitated a revision in terminology: endoscopically visible colitis associated dysplasia is the terminology suggested to replace DALM and adenoma-like lesion, while endoscopically invisible colitis associated dysplasia refers to flat dysplasia.23
Low-grade tubuloglandular adenocarcinoma This morphologic variant of inflammatory bowel diseaseassociated adenocarcinoma is notable for two reasons: (1) invasive carcinoma may be mistaken for dysplastic crypts, or worse still, entirely overlooked; and (2) although low-grade dysplasia is frequently observed, high-grade dysplasia is seldom seen. The invasive glands characteristically show circular or tubular profiles of fairly uniform diameter and a paucity of desmoplastic stroma (Figure 7).18 The cells lining the glands are generally cuboidal to low columnar, and the nuclei are bland without significant mitotic activity and minimal atypia. The changing perception of pre-neoplastic lesions in inflammatory bowel disease DALM e dysplasia associated lesion or mass, a term that may eventually turn obsolete, is generally used to designate dysplastic lesions that are recognizable on endoscopy.19 The presence of a DALM was correlated with invasive carcinoma in a high proportion of cases, and consequently total colectomy quickly
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Figure 8 Evolving changes to the management of inflammatory bowel disease-related dysplasia.
abnormality’ of inflammatory bowel disease-related neoplasia.28 Thus, p53 mutations may be detected in biopsies that lack morphologic evidence of dysplasia. In one study 13% of adenocarcinomas arising in Crohn’s disease and ulcerative colitis were associated with somatic IDH1 mutations, and a significant proportion of these neoplasms displayed a low-grade tubuloglandular pattern.29 While IDH1/2 mutations are identified in a wide variety of neoplasms including glioma, acute myeloid leukaemia and chondrosarcoma, intrahepatic cholangiocarcinoma represents the only other gastrointestinal tumour that harbours this mutation.30 IDH1 mutations were also identified in the precursor lesion, which tended to be of the serrated type.29 The identification of IDH1 mutations in inflammatory bowel disease-associated adenocarcinoma may have therapeutic implications e drugs that target the mutated forms of these genes are currently in phase 1 clinical trials.
Ancillary markers for the diagnosis of dysplasia The distinction of reactive epithelial changes from low-grade dysplasia and occasionally even high-grade dysplasia may be problematic and this has spurred an interest in developing biomarkers that might assist in this distinction. Foremost among these is p53. The p53 antibody does not target the mutated form of the protein, and instead detects the wild copy. Accordingly, p53 immunoreactivity is detected in nonneoplastic and reactive processes. Nevertheless, strong reactivity or presence of p53 in the upper 1/3rd or the surface mucosa would support the morphologic impression of dysplasia (see Figure 2).24 AMACR (a-Methylacyl coenzyme A racemase) is a mitochondrial and peroxisomal enzyme that plays an important role in fatty acid metabolism. In one study AMACR was detected in 96% of low-grade dysplasia, 80% of high-grade dysplasia and 71% of cancers.25,26 Although of some limited value, there is significant scepticism with regards to the value of these biomarkers, and they are generally not routinely used in clinical practice.
Therapy Invasive carcinoma is a ‘hard’ indication for total colectomy: dysplasia, in contrast, may not necessarily require a colectomy.
Genetics of inflammatory bowel disease related dysplasia Polypoid dysplastic lesion identified in a region never involved by inflammatory bowel disease The lesions generally represent sporadic adenomas or sessile serrated adenomas and may be safely treated with a polypectomy (Figure 8).
While there exists some overlap with the genetic abnormalities that underlie sporadic colon carcinoma, inflammatory bowel disease-related malignancy show some unique features, chiefly with regards to the timing and frequency of genetic alterations.7 In a significant majority of colon carcinomas, mutations of the APC gene is an early event in neoplastic progression, while p53 mutations are a late molecular event. The sequence of molecular events in inflammatory bowel disease-associated carcinoma appears to be different e p53 mutation is an early event.27 Of note, the molecular alterations are detected prior to morphologic evidence of dysplasia e a finding consistent with the ‘field
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Endoscopically visible colitis associated dysplasia Traditionally, a diagnosis of high-grade dysplasia would trigger a total colectomy. However, with the advent of advanced imaging the presence of even high-grade dysplasia may not necessarily require a total colectomy: endoscopic excision may suffice.31,32 An additional requirement for this colectomy-sparing paradigm
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11 Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983; 14: 931e68. 12 Dixon MF, Brown LJ, Gilmour HM, et al. Observer variation in the assessment of dysplasia in ulcerative colitis. Histopathology 1988; 13: 385e97. 13 Melville DM, Jass JR, Morson BC, et al. Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome. Hum Pathol 1989; 20: 1008e14. 14 Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett’s esophagus cohort. Am J Surg Pathol 2006; 30: 423e35. 15 Abraham SC, Taggart MW, Loftus EV, et al. Dysplasia-like epithelial atypia in ischemic bowel disease. Hum Pathol 2014; 45: 1348e57. 16 Andersen SN, Lovig T, Clausen OP, et al. Villous, hypermucinous mucosa in long standing ulcerative colitis shows high frequency of Kras mutations. Gut 1999; 45: 686e92. 17 Johnson DH, Khanna S, Smyrk TC, et al. Detection rate and outcome of colonic serrated epithelial changes in patients with ulcerative colitis or Crohn’s colitis. Aliment Pharmacol Ther 2014; 39: 1408e17. 18 Levi GS, Harpaz N. Intestinal low-grade tubuloglandular adenocarcinoma in inflammatory bowel disease. Am J Surg Pathol 2006; 30: 1022e9. 19 Blackstone MO, Riddell RH, Rogers BH, et al. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 1981; 80: 366e74. 20 Rubin PH, Friedman S, Harpaz N, et al. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology 1999; 117: 1295e300. 21 Engelsgjerd M, Farraye FA, Odze RD. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis. Gastroenterology 1999; 117: 1288e94. discussion 1488 e1291. 22 Torres C, Antonioli D, Odze RD. Polypoid dysplasia and adenomas in inflammatory bowel disease: a clinical, pathologic, and follow-up study of 89 polyps from 59 patients. Am J Surg Pathol 1998; 22: 275e84. 23 Rutter MD, Riddell RH. Colorectal dysplasia in inflammatory bowel disease: a clinicopathologic perspective. Clin Gastroenterol Hepatol 2014; 12: 359e67. 24 Wong NA, Mayer NJ, MacKell S, et al. Immunohistochemical assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis-related dysplasia. Histopathology 2000; 37: 108e14. 25 Dorer R, Odze RD. AMACR immunostaining is useful in detecting dysplastic epithelium in Barrett’s esophagus, ulcerative colitis, and Crohn’s disease. Am J Surg Pathol 2006; 30: 871e7. 26 Marx A, Wandrey T, Simon P, et al. Combined alpha-methylacyl coenzyme A racemase/p53 analysis to identify dysplasia in inflammatory bowel disease. Hum Pathol 2009; 40: 166e73. 27 Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology 2011; 140: 1807e16. 28 Galandiuk S, Rodriguez-Justo M, Jeffery R, et al. Field cancerization in the intestinal epithelium of patients with Crohn’s ileocolitis. Gastroenterology 2012; 142: 855e64. e858. 29 Hartman DJ, Binion D, Regueiro M, et al. Isocitrate dehydrogenase-1 is mutated in inflammatory bowel disease-associated intestinal adenocarcinoma with low-grade tubuloglandular histology but not in
is the absence of dysplasia in biopsies from the adjacent colon. Regardless, careful follow-up and enhanced surveillance is critical33: dysplasia arising in inflammatory bowel disease represents a field defect, and the remaining mucosa is at a high risk of developing malignancy. The current trend appears to favour conservative management, akin to the recent therapeutic approach to Barrett’s esophagus-associated neoplasia. Endoscopically invisible colitis-related dysplasia Historically, invasive carcinoma was detected in almost 1/3rd of patients with endoscopically invisible “flat” high-grade dysplasia. However, this data was from an era prior to the availability of high definition endoscopes, and presumably a significant proportion of these “flat” lesions are endoscopically recognizable on modern endoscopy. The management of endoscopically invisible colitis-associated dysplasia following chromoendoscopy is generally remains a total colectomy. The management strategies for low-grade dysplasia includes either colectomy or intensified surveillance: the decision rests on an open conversation between the patient and their physician. This decision is obviously complicated by the fact that the interobserver agreement for low-grade dysplasia among pathologists is generally poor. A REFERENCES 1 Jess T, Simonsen J, Jørgensen KT, et al. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012; 143: 375e81. e371 quiz e313e374. 2 Herrinton LJ, Liu L, Levin TR, et al. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology 2012; 143: 382e9. 3 Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138: 738e45. 4 Farraye FA, Odze RD, Eaden J, et al. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138: 746e74. 774 e741 e744; quiz e712e743. 5 Marion JF, Sands BE. The SCENIC consensus statement on surveillance and management of dysplasia in inflammatory bowel disease: praise and words of caution. Gastroenterology 2015; 148: 462e7. 6 Lutgens MWMD, van Oijen MGH, van der Heijden GJMG, et al. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm Bowel Dis 2013; 19: 789e99. 7 Beaugerie L. Inflammatory bowel disease therapies and cancer risk: where are we and where are we going? Gut 2012; 61: 476e83. 8 van den Broek FJ, Stokkers PC, Reitsma JB, et al. Random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis: low yield and absence of clinical consequences. Am J Gastroenterol 2014; 109: 715e22. 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: 1099e105. quiz 1340 e1091. 10 Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000; 47: 251e5.
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sporadic intestinal adenocarcinoma. Am J Surg Pathol 2014; 38: 1147e56. 30 Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 2012; 17: 72e9. 31 Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. N Engl J Med 2015; 372: 1441e52.
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32 Shergill AK, Farraye FA. Toward a consensus on endoscopic surveillance of patients with colonic inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014; 24: 469e81. 33 Wanders LK, Dekker E, Pullens B, et al. Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis. Clin Gastroenterol Hepatol 2014; 12: 756e64.
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Inflammatory bowel diseaserelated dysplasia: evolving diagnostic and therapeutic paradigms
however increasing evidence that targeted biopsies of lesions identified on a high-resolution endoscope represents a more efficient means of detecting dysplasia, and random biopsies do not increase the yield of neoplasia.7,8
Stratification of risk in IBD The degree of cancer risk is modulated by several factors including the extent of colitis, duration of disease, the presence of primary sclerosing cholangitis, and the severity of inflammation: these features assist in stratifying risk and guide the management of patients. Patients with pancolitis and primary sclerosing cholangitis are at the highest risk of malignancy, while patients with isolated proctitis are at no additional risk of cancer. Thus, patients with proctitis do not require cancer surveillance while those with primary sclerosing cholangitis and pancolitis are placed on an accelerated screening protocol. The severity of microscopic inflammation over time has also been shown to be an independent risk factor for colorectal neoplasia among patients with ulcerative colitis.9
Vikram Deshpande
Abstract Patients with inflammatory bowel disease show an excess colon cancer incidence and mortality. Colonoscopy with biopsies represents the most robust strategy for decreasing the risk of malignancy. Targeted biopsies of lesions identified on a high-resolution endoscope and chromoendoscopy is now believed to be a more efficient means of detecting dysplasia, and random biopsies do not increase the yield of neoplasia. In clinical practice, the diagnosis of dysplasia is based on a constellation of changes that include cytologic, architectural and maturational abnormalities. Morphologically, most dysplasia is of the adenomatous type. The distinction of low-grade dysplasia from reactive epithelial changes remains a significant and sometime an insurmountable problem. Although p53 immunohistochemistry has been proposed as a biomarker for dysplasia, positive staining reactive conditions significantly limits its utility as a marker of dysplasia. The advent of high resolution endoscopes and chromoendoscopy allows for the visualization of the vast majority of dysplastic lesions, leaving only a minority of lesions are endoscopically invisible. Advances in screening and endoscopic resection techniques now permit conservative management of endoscopically visible dysplastic lesion, including some cases of high-grade dysplasia.
Diagnosis of dysplasia Endoscopic appearance Endoscopically the appearance is highly variable and includes nodules, plaque-like lesions, a filiform appearance, as well as stricture formation (Figure 1a and b). Histology Colonic biopsies are grouped into five categories: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, highgrade dysplasia and invasive carcinoma. A revised Vienna classification is used in many centers in Europe.10 The classification and criteria for dysplasia in inflammatory bowel disease were proposed by Riddell and colleagues in 1983.11 Intra- and inter-observer variability in the interpretation of biopsy specimens for dysplasia in inflammatory bowel disease is well documented, even among experienced gastrointestinal pathologists.12,13 In general, levels of agreement are highest for the category of high-grade dysplasia and for biopsy specimens considered negative for dysplasia, but are lowest at the lower end of the spectrum (e.g., indefinite for dysplasia versus low-grade dysplasia).
Keywords dysplasia; inflammatory bowel disease; p53
Introduction While the increased risk of cancer in patients with inflammatory bowel disease is widely acknowledged, over the last decade its become increasingly apparent that the extent of the risk may have been over-estimated, a consequence of the bias introduced by the study of referral center cohorts. A recent Danish population based study found no excess risk of cancer in ulcerative colitis.1 This may well be a consequence of better surveillance, more robust control of inflammation, as well as use of agents such as 5-aminosalicylates, a potentially chemopreventive agent. On the other hand, a recent study from Northern California found excess colon cancer incidence and mortality in patients with inflammatory bowel disease.2 Regular colonoscopy with biopsies represents the most robust strategy for decreasing the risk of malignancy.3e6 Until recently, multiple random biopsies from diseased/previously diseased colon was the standard of care. There is
Defining dysplasia Dysplasia, also referred to as intraepithelial neoplasia, is a preneoplastic lesion that puts the patient at a high risk of invasive carcinoma, both at the site of biopsy and other sites within the diseased organ. Dysplasia is defined as unequivocally neoplastic epithelium confined to the basement membrane. This definition has little practical value since evaluating the basement membrane and defining ‘unequivocally neoplastic’ represent significant and sometimes insurmountable challenges. In clinical practice the diagnosis of dysplasia is based on a constellation of changes that include cytologic, architectural and maturational abnormalities. Cytologically, dysplastic cells are characterized by nuclear stratification, cellular crowding, as well as hyperchromatic and enlarged nuclei (Figures 2 and 3). Common architectural abnormalities include small glandular profiles, irregularly shaped glands, glandular crowding, crypt budding
Vikram Deshpande MD Associate Pathologist, Department of Pathology, Massachusetts General Hospital and Associate Professor of Pathology, Harvard Medical School, Boston, MA, USA. Conflicts of interest: none declared.
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Figure 1 (a and b) Endoscopically visible dysplasia arising in inflammatory bowel disease (arrows).
and cribriforming, the presence of back-to-back glands with varying degrees of stromal extinction, and a villiform surface (Figures 4 and 5). It should be noted that severe architectural changes are typically seen only in high-grade dysplasia. The lack of maturation represents a key feature that distinguishes a reactive process (also see below) from dysplasia. Within normal colonic epithelium, proliferation is confined to the crypt base. It is notable that stem cells are identified at the bottom of the crypt and proliferative activity is noted immediately above this region e thus Ki67 positive cells are confined to the bottom 1/3rd of the crypt. This contrasts with the location of stem cells and the proliferative zone in the stomach e situated in the higher regions of the mucosa. The colonic cells above the crypt base show progressively smaller nuclei and differentiate
into goblet cells, absorptive and endocrine cells. This pattern of acquisition of terminally differentiated cells is often referred to as maturation. Dysplastic epithelium often lacks maturation, instead ‘proliferative-type’ epithelium is identified within the upper 1/3rd of the crypts, and more significantly, on the surface epithelium. While lack of maturation distinguishes dysplasia from reactive epithelium, it should be noted that the expanded proliferative zone may extend into the upper half of the crypt in regenerative states (Figure 6). Furthermore, it should be recognized that the length of the crypts may be significantly reduced in cases with marked regenerative changes e as is often found adjacent to an ulcer. In this scenario the proliferative zone may extend extremely close to the surface epithelium, as a result only subtle (or rarely none) evidence of maturation may be evident
Figure 2 Ulcerative colitis with low-grade dysplasia. The image shows lack of maturation. However, the polarity of the cells is preserved (a). Immunohistochemistry performed on this case show strong reactivity for p53. The reactivity extends to the upper half of the crypts (b).
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adenomas i.e. show an adenomatous appearance, and are thus readily diagnosed as dysplasia. However, regenerative epithelium may show enlarged hyperchromatic nuclei with stratification, a high nuclear to cytoplasmic ratio, and resemble tubular adenomas and dysplasia. Broadly speaking, there two reason for uncertainty and a diagnosis of indefinite for dysplasia: (1) severe inflammation/ ulceration, (2) technical reasons e a tangential cut, lack of surface epithelium, poor orientation, poor fixation, and cautery artifacts. An extremely helpful feature in making this distinction is the abrupt demarcation between dysplastic and benign epithelium. The atypia in regenerative epithelium merges gradually with adjacent normal epithelial cells. It is unwise to render a diagnosis of dysplasia in the presence of an ulcer, unless there is unequivocal evidence of high-grade dysplasia or carcinoma. It should be noted that the erosion/ulcer may not be included in the biopsy, and thus other evidence should be sought such as the presence fibrinopurulent exudate or granulation tissue. The presence of intraepithelial/intramucosal neutrophils do not exclude a diagnosis of dysplasia. The potential for regenerative epithelial changes to mimic dysplasia was highlighted in a recent study of ischaemic enterocolitis.15 Based on cytologic criteria alone these authors were unable to distinguish dysplasia from regenerative mucosa. Interestingly, neither p53 (also see below) nor Ki67 could assist in this distinction, bringing into question the utility of these markers in the diagnosis of dysplasia.15 A helpful rule of thumb is to avoid evaluating the atypical epithelium in isolation; instead it is prudent to judge the epithelium by the company it keeps.
Figure 3 Ulcerative colitis with dysplasia. The adenomatous appearance as well as the lack of maturation is obvious. The focal loss of polarity of the surface epithelial cells (on the right side of the image) is suggestive of high-grade dysplasia.
(Figure 6). This accounts for the reluctance of pathologists to render an unequivocal diagnosis of dysplasia on biopsies obtained immediately adjacent to an ulcer. The convention that a diagnosis of dysplasia requires the involvement of the surface by neoplastic epithelium has been challenged e the so-called basal crypt dysplasia.14 However, the concept of colonic basal crypt dysplasia is generally not accepted. Nevertheless, if significant atypia is identified in the basal crypt region, every effort should be made to identify surface involvement, and this generally involves requesting additional levels.
Distinction of low-grade from high-grade dysplasia This is one of the more vexing problems associated with the diagnosis of dysplasia in inflammatory bowel disease. The distinction is central to many key management decisions e a diagnosis of high-grade dysplasia may trigger total colectomy, while the diagnosis of low-grade dysplasia may require only accelerated surveillance. Unfortunately, there is no single feature that distinguishes low-grade from high-grade dysplasia,
Distinction of reactive from dysplastic epithelium and the indefinite for dysplasia category The term ‘indefinite for dysplasia’ is not a diagnostic category, but simply a placeholder with the understanding that subsequent biopsies will provide unequivocal evidence of dysplasia or lack thereof. Fortunately, unlike the upper gastrointestinal tract, the majority of dysplastic lesions resemble sporadic tubular
Figure 4 Ulcerative colitis with high-grade dysplasia. The marked architectural abnormalities suggest high-grade dysplasia e glandular crowding, budding and stromal extinction (a). High power view show cells with vesicular nuclei and prominent nucleoli. However, the polarity is largely intact (b).
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Figure 5 Colitis with high-grade dysplasia (a and b). Some of the glands display a serrated profile.
the distinction requires evaluation of a constellation of features. The architectural alterations are more severe in highgrade dysplasia e changes such as crypt crowding, budding and irregularly shaped crypts are indicative of high-grade dysplasia (see Figure 4). Another useful criterion is the presence of full thickness nuclear stratification in high-grade dysplasia: nuclei of low-grade dysplasia they are generally confined to the base of the epithelium, while with high-grade dysplasia are haphazardly distributed in both the basal as well as the apical regions of the epithelium. The nuclei in lowgrade dysplasia tend to be penicillate, while in high-grade dysplasia the cells appear more “undifferentiated” with round to oval nuclei, coarse chromatin, and enlarged nucleoli (see
Figure 4). Loss of polarity is another key feature of high-grade dysplasia. Normal columnar cells and their nuclei are placed perpendicular to the basement membrane. The loss of this characteristic relationship between the cells and the basement membrane constitutes loss of polarity. The presence of atypical mitoses extending to the surface is yet another feature of highgrade dysplasia. The quantitative aspects of this distinction have not been addressed, although it is often stated (with little corroborative evidence) that a diagnosis of high-grade dysplasia requires at least 2 crypts showing unequivocal changes of high-grade dysplasia. It should be noted that the changes of Crohn’s related-dysplasia seen in Crohn’s disease are generally similar to that seen in ulcerative colitis.
Figure 6 Ulcerative colitis with reactive epithelial changes. The epithelium immediately adjacent to the ulcer is similar to an adenoma (a). Focally, the adenomatous epithelium appears to extend to the surface epithelium (b). Incomplete maturation is seen (arrow). The basal glands e the proliferative region of the mucosa e is indistinguishable from an adenoma (c).
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Figure 7 Low-grade tubuloglandular adenocarcinoma. Note the well formed glandular structures infiltrating into the submucosa (a). Invasive glands in the submucosa (b).
Other less common forms of dysplasia The epithelium of hypermucinous dysplasia may show small banal appearing basally placed nuclei with abundant apical mucin, often in a papillary configuration, an appearance that could easily be dismissed as reactive.16 Fortunately, this is typically a focal finding, and foci of adenomatous dysplasia are invariably found elsewhere in the biopsy. The presence of mucinous epithelium, particularly if villiform in contour, is suggestive of dysplasia. Pure hypermucinous dysplasia is rare. The natural history of pure hypermucinous dysplasia is unknown. Whether serrated colonic mucosa lacking cellular atypia i.e. conventional dysplasia increases the risk of malignancy remains uncertain.17 These changes are referred to as serrated epithelial changes, an attempt to distinguish this lesion from sessile serrated adenoma and traditional serrated adenoma. Nevertheless, given the concern that serrated epithelial changes may increase the risk of colon carcinoma, it appears prudent for pathologist to document this finding.17
became the standard of care for these patients. However, this paradigm did not take into account sporadic adenomas in patients with inflammatory bowel disease. Mistaking a sporadic adenoma for the more ominous DALM would inadvertently subject the patient to a total colectomy. These sporadic adenomas were subsequently designated as adenoma-like lesions, and the patients were treated conservatively.19e21 Lesions that appeared invisible to the endoscopist were designated as flat dysplasia, and until recently the standard of care for ‘flat’ highgrade dysplasia was total colectomy. Given the clinical significance of this distinction, numerous attempts were made to uncover histologic differences between DALMs and sporadic adenomas. In one study DALMs were more frequently associated with tubulovillous or villous architecture, an admixture of normal and dysplastic epithelium at the surface of the polyps, and increased lamina propria mononuclear inflammation.22 Dysplasia in the adjacent ‘flat’ mucosa also favoured DALM, as did the combination of strong p53 expression and absent or weak beta-catenin expression. However, these criteria were neither robust nor objective, and thus were seldom used in clinical practice. Instead, the onus for this distinction lay with the endoscopist: adenoma-like dysplastic lesions are wellcircumscribed, smooth or papillary, sessile or pedunculated polyps while DALMs could be velvety patches, plaques, nodules, mucosal thickenings, stricturing lesions, and broad-based masses. A paradigm shift to the therapeutic algorithm has been spurred by the availability of high-resolution white-light endoscopes as well as newer endoscopic techniques, particularly chromoendoscopy, the latter now considered standard of care when screening for malignancy in inflammatory bowel disease. Accordingly, lesions that might have been invisible in the past are both readily visualized and the borders defined, permitting endoscopic resection. This paradigm shift has also necessitated a revision in terminology: endoscopically visible colitis associated dysplasia is the terminology suggested to replace DALM and adenoma-like lesion, while endoscopically invisible colitis associated dysplasia refers to flat dysplasia.23
Low-grade tubuloglandular adenocarcinoma This morphologic variant of inflammatory bowel diseaseassociated adenocarcinoma is notable for two reasons: (1) invasive carcinoma may be mistaken for dysplastic crypts, or worse still, entirely overlooked; and (2) although low-grade dysplasia is frequently observed, high-grade dysplasia is seldom seen. The invasive glands characteristically show circular or tubular profiles of fairly uniform diameter and a paucity of desmoplastic stroma (Figure 7).18 The cells lining the glands are generally cuboidal to low columnar, and the nuclei are bland without significant mitotic activity and minimal atypia. The changing perception of pre-neoplastic lesions in inflammatory bowel disease DALM e dysplasia associated lesion or mass, a term that may eventually turn obsolete, is generally used to designate dysplastic lesions that are recognizable on endoscopy.19 The presence of a DALM was correlated with invasive carcinoma in a high proportion of cases, and consequently total colectomy quickly
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Figure 8 Evolving changes to the management of inflammatory bowel disease-related dysplasia.
abnormality’ of inflammatory bowel disease-related neoplasia.28 Thus, p53 mutations may be detected in biopsies that lack morphologic evidence of dysplasia. In one study 13% of adenocarcinomas arising in Crohn’s disease and ulcerative colitis were associated with somatic IDH1 mutations, and a significant proportion of these neoplasms displayed a low-grade tubuloglandular pattern.29 While IDH1/2 mutations are identified in a wide variety of neoplasms including glioma, acute myeloid leukaemia and chondrosarcoma, intrahepatic cholangiocarcinoma represents the only other gastrointestinal tumour that harbours this mutation.30 IDH1 mutations were also identified in the precursor lesion, which tended to be of the serrated type.29 The identification of IDH1 mutations in inflammatory bowel disease-associated adenocarcinoma may have therapeutic implications e drugs that target the mutated forms of these genes are currently in phase 1 clinical trials.
Ancillary markers for the diagnosis of dysplasia The distinction of reactive epithelial changes from low-grade dysplasia and occasionally even high-grade dysplasia may be problematic and this has spurred an interest in developing biomarkers that might assist in this distinction. Foremost among these is p53. The p53 antibody does not target the mutated form of the protein, and instead detects the wild copy. Accordingly, p53 immunoreactivity is detected in nonneoplastic and reactive processes. Nevertheless, strong reactivity or presence of p53 in the upper 1/3rd or the surface mucosa would support the morphologic impression of dysplasia (see Figure 2).24 AMACR (a-Methylacyl coenzyme A racemase) is a mitochondrial and peroxisomal enzyme that plays an important role in fatty acid metabolism. In one study AMACR was detected in 96% of low-grade dysplasia, 80% of high-grade dysplasia and 71% of cancers.25,26 Although of some limited value, there is significant scepticism with regards to the value of these biomarkers, and they are generally not routinely used in clinical practice.
Therapy Invasive carcinoma is a ‘hard’ indication for total colectomy: dysplasia, in contrast, may not necessarily require a colectomy.
Genetics of inflammatory bowel disease related dysplasia Polypoid dysplastic lesion identified in a region never involved by inflammatory bowel disease The lesions generally represent sporadic adenomas or sessile serrated adenomas and may be safely treated with a polypectomy (Figure 8).
While there exists some overlap with the genetic abnormalities that underlie sporadic colon carcinoma, inflammatory bowel disease-related malignancy show some unique features, chiefly with regards to the timing and frequency of genetic alterations.7 In a significant majority of colon carcinomas, mutations of the APC gene is an early event in neoplastic progression, while p53 mutations are a late molecular event. The sequence of molecular events in inflammatory bowel disease-associated carcinoma appears to be different e p53 mutation is an early event.27 Of note, the molecular alterations are detected prior to morphologic evidence of dysplasia e a finding consistent with the ‘field
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Endoscopically visible colitis associated dysplasia Traditionally, a diagnosis of high-grade dysplasia would trigger a total colectomy. However, with the advent of advanced imaging the presence of even high-grade dysplasia may not necessarily require a total colectomy: endoscopic excision may suffice.31,32 An additional requirement for this colectomy-sparing paradigm
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11 Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical applications. Hum Pathol 1983; 14: 931e68. 12 Dixon MF, Brown LJ, Gilmour HM, et al. Observer variation in the assessment of dysplasia in ulcerative colitis. Histopathology 1988; 13: 385e97. 13 Melville DM, Jass JR, Morson BC, et al. Observer study of the grading of dysplasia in ulcerative colitis: comparison with clinical outcome. Hum Pathol 1989; 20: 1008e14. 14 Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett’s esophagus cohort. Am J Surg Pathol 2006; 30: 423e35. 15 Abraham SC, Taggart MW, Loftus EV, et al. Dysplasia-like epithelial atypia in ischemic bowel disease. Hum Pathol 2014; 45: 1348e57. 16 Andersen SN, Lovig T, Clausen OP, et al. Villous, hypermucinous mucosa in long standing ulcerative colitis shows high frequency of Kras mutations. Gut 1999; 45: 686e92. 17 Johnson DH, Khanna S, Smyrk TC, et al. Detection rate and outcome of colonic serrated epithelial changes in patients with ulcerative colitis or Crohn’s colitis. Aliment Pharmacol Ther 2014; 39: 1408e17. 18 Levi GS, Harpaz N. Intestinal low-grade tubuloglandular adenocarcinoma in inflammatory bowel disease. Am J Surg Pathol 2006; 30: 1022e9. 19 Blackstone MO, Riddell RH, Rogers BH, et al. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 1981; 80: 366e74. 20 Rubin PH, Friedman S, Harpaz N, et al. Colonoscopic polypectomy in chronic colitis: conservative management after endoscopic resection of dysplastic polyps. Gastroenterology 1999; 117: 1295e300. 21 Engelsgjerd M, Farraye FA, Odze RD. Polypectomy may be adequate treatment for adenoma-like dysplastic lesions in chronic ulcerative colitis. Gastroenterology 1999; 117: 1288e94. discussion 1488 e1291. 22 Torres C, Antonioli D, Odze RD. Polypoid dysplasia and adenomas in inflammatory bowel disease: a clinical, pathologic, and follow-up study of 89 polyps from 59 patients. Am J Surg Pathol 1998; 22: 275e84. 23 Rutter MD, Riddell RH. Colorectal dysplasia in inflammatory bowel disease: a clinicopathologic perspective. Clin Gastroenterol Hepatol 2014; 12: 359e67. 24 Wong NA, Mayer NJ, MacKell S, et al. Immunohistochemical assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis-related dysplasia. Histopathology 2000; 37: 108e14. 25 Dorer R, Odze RD. AMACR immunostaining is useful in detecting dysplastic epithelium in Barrett’s esophagus, ulcerative colitis, and Crohn’s disease. Am J Surg Pathol 2006; 30: 871e7. 26 Marx A, Wandrey T, Simon P, et al. Combined alpha-methylacyl coenzyme A racemase/p53 analysis to identify dysplasia in inflammatory bowel disease. Hum Pathol 2009; 40: 166e73. 27 Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology 2011; 140: 1807e16. 28 Galandiuk S, Rodriguez-Justo M, Jeffery R, et al. Field cancerization in the intestinal epithelium of patients with Crohn’s ileocolitis. Gastroenterology 2012; 142: 855e64. e858. 29 Hartman DJ, Binion D, Regueiro M, et al. Isocitrate dehydrogenase-1 is mutated in inflammatory bowel disease-associated intestinal adenocarcinoma with low-grade tubuloglandular histology but not in
is the absence of dysplasia in biopsies from the adjacent colon. Regardless, careful follow-up and enhanced surveillance is critical33: dysplasia arising in inflammatory bowel disease represents a field defect, and the remaining mucosa is at a high risk of developing malignancy. The current trend appears to favour conservative management, akin to the recent therapeutic approach to Barrett’s esophagus-associated neoplasia. Endoscopically invisible colitis-related dysplasia Historically, invasive carcinoma was detected in almost 1/3rd of patients with endoscopically invisible “flat” high-grade dysplasia. However, this data was from an era prior to the availability of high definition endoscopes, and presumably a significant proportion of these “flat” lesions are endoscopically recognizable on modern endoscopy. The management of endoscopically invisible colitis-associated dysplasia following chromoendoscopy is generally remains a total colectomy. The management strategies for low-grade dysplasia includes either colectomy or intensified surveillance: the decision rests on an open conversation between the patient and their physician. This decision is obviously complicated by the fact that the interobserver agreement for low-grade dysplasia among pathologists is generally poor. A REFERENCES 1 Jess T, Simonsen J, Jørgensen KT, et al. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012; 143: 375e81. e371 quiz e313e374. 2 Herrinton LJ, Liu L, Levin TR, et al. Incidence and mortality of colorectal adenocarcinoma in persons with inflammatory bowel disease from 1998 to 2010. Gastroenterology 2012; 143: 382e9. 3 Farraye FA, Odze RD, Eaden J, et al. AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138: 738e45. 4 Farraye FA, Odze RD, Eaden J, et al. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138: 746e74. 774 e741 e744; quiz e712e743. 5 Marion JF, Sands BE. The SCENIC consensus statement on surveillance and management of dysplasia in inflammatory bowel disease: praise and words of caution. Gastroenterology 2015; 148: 462e7. 6 Lutgens MWMD, van Oijen MGH, van der Heijden GJMG, et al. Declining risk of colorectal cancer in inflammatory bowel disease: an updated meta-analysis of population-based cohort studies. Inflamm Bowel Dis 2013; 19: 789e99. 7 Beaugerie L. Inflammatory bowel disease therapies and cancer risk: where are we and where are we going? Gut 2012; 61: 476e83. 8 van den Broek FJ, Stokkers PC, Reitsma JB, et al. Random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis: low yield and absence of clinical consequences. Am J Gastroenterol 2014; 109: 715e22. 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: 1099e105. quiz 1340 e1091. 10 Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000; 47: 251e5.
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sporadic intestinal adenocarcinoma. Am J Surg Pathol 2014; 38: 1147e56. 30 Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 2012; 17: 72e9. 31 Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. N Engl J Med 2015; 372: 1441e52.
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32 Shergill AK, Farraye FA. Toward a consensus on endoscopic surveillance of patients with colonic inflammatory bowel disease. Gastrointest Endosc Clin N Am 2014; 24: 469e81. 33 Wanders LK, Dekker E, Pullens B, et al. Cancer risk after resection of polypoid dysplasia in patients with longstanding ulcerative colitis: a meta-analysis. Clin Gastroenterol Hepatol 2014; 12: 756e64.
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