Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis.
* Context.--Colorectal cancer, the most lethal long-term
complication of chronic inflammatory bowel disease (IBD), is the
culmination of a complex sequence of molecular and histologic
derangements of the intestinal epithelium that are initiated and at
least partially sustained by chronic inflammation. Dysplasia, the
earliest histologic manifestation of this process, plays an important
role in cancer prevention by providing the first clinical alert that
this sequence is underway and serving as an endpoint in colonoscopic
surveillance of patients at high risk for colorectal cancer.
Objective.--To review the histology, nomenclature, clinical implications, and molecular pathogenesis of dysplasia in IBD.
Data Source.--Literature review and illustrations from case material.
Conclusions.--The diagnosis and grading of dysplasia in endoscopic surveillance biopsies play a decisive role in the management of patients with IBD. Although interpathologist variation, endoscopic sampling problems, and incomplete information regarding the natural history of dysplastic lesions are important limiting factors, indirect evidence that surveillance may be an effective means of reducing cancer-related mortality in the population with IBD has helped validate the histologic criteria, nomenclature, and clinical recommendations that are the basis of current practice among pathologists and clinicians. Emerging technologic advances in endoscopy may permit more effective surveillance, but ultimately the greatest promise for cancer prevention in IBD lies in expanding our thus far limited understanding of the molecular pathogenetic relationships between neoplasia and chronic inflammation.
(Arch Pathol Lab Med. 2010;134:876-895)
|Article Type:||Disease/Disorder overview|
Colorectal cancer (Development and progression)
Colorectal cancer (Diagnosis)
Colorectal cancer (Care and treatment)
Inflammatory bowel diseases (Complications and side effects)
Inflammatory bowel diseases (Development and progression)
Polydorides, Alexandros D.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: June, 2010 Source Volume: 134 Source Issue: 6|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
Since the first published reports of an association between
colorectal cancer (CRC) and the 2 major forms of idiopathic chronic
inflammatory bowel disease (IBD), ulcerative colitis (UC) in 1925 (1)
and Crohn disease (CD) in 1948, (2) CRC has become recognized as a
leading cause of long-term mortality in men and women with IBD, most of
whom become victims by middle age. (3) For the past 3 decades, efforts
at cancer prevention in this population have been based on an empirical
strategy of scheduled colonoscopic surveillance examinations with
biopsies to identify dysplasia, the earliest recognizable precursor of
CRC and the most reliable marker of imminent cancer risk. Ideally, the
rationale of surveillance is to allow most patients whose biopsy
specimens remain free of dysplasia to avoid colectomy while enabling
those with dysplasia to undergo surgery before the development of
incurable CRC. Although validation of this strategy has been based
largely on indirect evidence, surveillance has been embraced by
professional societies as the standard of care for patients at high risk
for CRC (4-7) and has been broadly implemented within the
More than any other factor, it is the pathologist's biopsy interpretations that guide the management of patients during surveillance. As a result, it is incumbent on general and specialized gastrointestinal pathologists alike to be familiar with the morphology, nomenclature, and clinical implications of dysplasia in IBD.
Colorectal cancer in IBD is also the prototype of the inflammation-dysplasia-cancer sequence in the lower gastrointestinal tract and the culmination of unique histogenetic and molecular pathways, the details of which cannot be simply extrapolated directly from the sporadic adenoma-cancer sequence. Familiarity with its pathogenesis is the key to future improvements in diagnosis and chemoprevention as well as basic advances in our understanding of carcinogenesis.
COLORECTAL NEOPLASIA IN IBD
The risk of CRC in patients with CD was overlooked in early studies because of failure to evaluate cases with colitis as a separate risk group and to take into account the effects of early colectomy. However, there is now compelling evidence that the magnitude of risk associated with CD is similar to that for UC of comparable duration and extent. (15-21) Direct comparative hospital-based studies of CRC in UC and CD (17-19,21) have reported close similarities with respect to multiple clinical and pathologic parameters. A British study that compared the incidence of CRC in 2 identically selected cohorts of patients with extensive UC and colonic CD (18) reported a cumulative incidence of CRC of 8% at 22 years from onset of symptoms in the CD group and 7% at 20 years from onset of symptoms in the UC group. Finally, a recent meta-analysis (20) has estimated the relative risk for CRC in patients with CD and any colonic involvement to be 4.5, similar to that in UC, even without factoring in the effects of early colectomy.
Colorectal cancer complicating extensive UC or pancolitis is diagnosed at an average age of approximately 45 years, or 15 to 20 years younger than patients with cancer in the general population, (22-24) corresponding to a mean colitis-cancer interval of approximately 20 years. The onset of IBD in childhood or adolescence poses a substantial cumulative risk for development of CRC, as high as 40% in 1 study, (23) and accounts for nearly one-third of all IBD-related cancer cases. However, most authorities do not consider early disease onset to be an independent risk factor per se but a reflection of prolonged risk exposure and of high prevalence of pancolitis in children. (25)
Approximately 80% of cancers in UC occur in the setting of pancolitis or colitis extending as far proximally as the hepatic flexure (extensive colitis). (9) Left-sided UC confers an intermediate degree of risk for neoplasia, whereas proctitis and proctosigmoiditis confer little or none. (23,26) The onset of left-sided colitis and of associated CRC each occurs 5 to 10 years later, on average, than for pancolitis, but the mean 20-year colitis-cancer interval remains the same. (27)
The intensity of microscopic inflammation in colonic biopsy specimens has been implicated as an independent risk factor for development of neoplasia in 2 studies, a case-control study from St Marks Hospital (London, United Kingdom) (28) and a cohort study from The Mount Sinai Hospital (New York, New York). (29) Using similar scales to grade inflammation in colonic biopsy specimens, both groups concluded that the actuarial risk of neoplasia increases 3- to 5-fold for every unit increase in the grade of inflammation. The seemingly contradictory fact that CRC is often diagnosed in patients with clinically quiescent disease may be explained by (1) the greater likelihood that they will retain their colon indefinitely, (2) their lower likelihood of seeking regular medical care, (30) and (3) poor correlation between microscopic and clinical indices of disease severity. (31-34)
The development of neoplasia in IBD may reflect underlying genetic predispositions in some cases. Case-control (35) and cohort studies (36) have reported a greater than 2-fold increased risk of CRC in patients with IBD who have first-degree relatives with CRC and a 9-fold increased risk if the relatives had CRC before age 50 years. (36)
Synchronous primary sclerosing cholangitis in UC confers a substantially increased risk for development of CRC according to most studies, though not all. (16) One Swedish population study (37) reported the incidence of CRC 10, 20, and 30 years after the diagnosis of UC to be 10%, 33%, and 40%, respectively. Nevertheless, since primary sclerosing cholangitis is prevalent in patients with extensive but mild or asymptomatic colitis, it may be serving merely as a surrogate marker for long-standing extensive UC rather than as an independent risk factor for CRC. (38)
Pathology of CRC in IBD
Inflammatory bowel disease-associated CRC occurs in a background of chronically inflamed mucosa, although direct endoscopic visualization, compared with microscopic assessment, often underestimates the intensity and extent of inflammation. (32) Most studies (9,39-42) have reported CRC cases in UC predominated in the left colon, especially the sigmoid colon and rectum, but others (17,22,26,43) have reported a roughly even distribution of lesions on either side of the splenic flexure in both UC and CD.
Compared with sporadic CRC, cancer in IBD is macroscopically heterogeneous and tends to be poorly delimited, irregular, and multifocal. Some cases mimic inflammatory strictures, ulcers, and inflammatory polyps, while others are deceptively flat and inconspicuous. (9,44) The frequency of multiple synchronous cancers in IBD is 10% to 30%, especially in younger patients, and the simultaneous occurrence of 3 or more lesions is not unusual; by comparison, the frequency of 2 synchronous cancers in the general population is 3% to 5% and that of 3 or more is virtually nil. (17,26,40,43,45,46)
Most cases of CRC in IBD are histologically conventional adenocarcinomas. However, mucinous adenocarcinomas account for 15% to 30% of these cancers, compared with 10% to 15% in the general population, (17,19) and signet ring cell adenocarcinomas account for up to 7%, compared with approximately 1% in the general population. (17) In addition, extremely well-differentiated adenocarcinomas that are rarely encountered outside the setting of IBD account for 11% of IBD-associated intestinal cancers resected at The Mount Sinai Hospital (Figure 1, A and B). (47)
Pathologists of the precolonoscopic era were the first to recognize dysplasia as a precursor of CRC in IBD (2,48) and to propose periodic monitoring for dysplasia with rectal biopsies as a means of controlling cancer mortality. (48) These observations led to the first endoscopic surveillance program for patients with UC at St Mark's Hospital in 1971, (49) which became emulated widely and has now become the standard of care for patients with UC and colonic CD who are at high risk for CRC. (4,6,7,50,51)
The evidence supporting the role of dysplasia in the pathogenesis of CRC in IBD can be summarized as follows. (1) Studies of resected colons have shown that dysplasia occurs in proximity to cancer in approximately 90% of resected colons, including nearly all cases with multiple cancers, (17,40,45,52,53) and elsewhere in the colon in approximately 75% of cases of UC (23,40,41,43) and 27% to 100% of cases of CD. (53-57) (2) Patients with IBD who undergo colectomy with a prior biopsy diagnosis of dysplasia are diagnosed with CRC in 20% to 50% of cases. (58-61) (3) Nearly all published results of endoscopic surveillance programs have documented neoplastic progression to CRC or high-grade dysplasia by way of lower grades of dysplasia. (4) Inflammatory bowel disease-associated dysplasia and CRC share common gene mutations and altered gene expression profiles. (62,63) (5) Although ethical constraints preclude randomized prospective studies to prove that endoscopic surveillance can reduce the incidence of CRC or prolong survival in the population with IBD, direct evidence from case-control studies indicates that surveillance leads to the detection of cancers at relatively early stages, and circumstantial evidence suggests that it is an effective strategy to reduce cancer-related mortality. (64)
[FIGURE 1 OMITTED]
CLASSIFICATION AND MORPHOLOGY
Colorectal dysplasia may be defined as an unequivocal neoplastic alteration of the intestinal epithelium that remains restricted within the basement membrane within which it originated. (65) It is synonymous with the term intraepithelial neoplasia adopted by the World Health Organization (66) and Vienna (67) nomenclature systems for gastrointestinal neoplasia but is more widely used in the United States. According to a standardized classification system for dysplasia, established in a landmark paper by Riddell et al (65) in 1983, nonneoplastic mucosa, whether normal or reactive, is classified as "negative for dysplasia"; dysplasia is subclassified as low-grade dysplasia (LGD) or high-grade dysplasia (HGD); and mucosa that cannot be classified with certainty as positive or negative for dysplasia is classified as "indefinite for dysplasia (IND)."
The defining histologic features of dysplastic colorectal epithelium in IBD are analogous to those of sporadic adenomatous polyps and include (1) nuclear atypism manifested by increased nuclear to cytoplasmic ratios, crowding, and hyperchromasia; (2) cytoplasmic abnormalities suggesting altered differentiation and clonality, such as diminished or, conversely, excessive goblet cell mucin; and (3) abnormal growth patterns indicating faulty control of cellular proliferation, including glandular crowding, tubular or villiform architecture and the absence of normal base-to-surface epithelial maturation.
Dysplastic Versus Reactive Epithelium
The distinction in endoscopic biopsy specimens between dysplasia and reactive epithelial changes elicited by colitis can be challenging, especially when there is a background of active or resolving inflammation. Nevertheless, the notion that a diagnosis of dysplasia may simply be disregarded when it occurs in the setting of active inflammation is baseless. In fact, truly problematic cases are the exception rather than the rule. By analogy, pathologists rarely have difficulty recognizing even the most severely inflamed adenomas.
One of the hallmarks of reactive crypts is a base-to-surface epithelial maturation gradient in which phenotypically immature, mitotically active, basal colonocytes differentiate into mature surface cells featuring small, normochromatic nuclei, distinct absorptive and goblet cell phenotypes, and absent mitoses (Figure 2, A through D). In the setting of active or resolving inflammation, the proportions of immature cells tend to expand and to displace the maturation gradient closer to the surface. Dysplastic epithelium, in contrast, extends uniformly along the crypt axis and surface epithelium with little or no surface maturation. An important exception is villous dysplasia, which often exhibits maturation along the villous tips. Other features that favor dysplasia over reactive mucosa include diffuse nuclear hyperchromasia, macronucleoli, atypical mitotic figures, loss of cellular polarity, and dirty intraluminal necrosis. Nondysplastic epithelium also tends to be more responsive to local variations in inflammatory activity than dysplastic epithelium. As a result, foci of cryptitis or erosions in the absence of dysplasia elicit maturation microgradients, that is, transitions from regenerative to mature colonocytes within a single crypt or group of adjoining crypts. Dysplastic epithelium usually manifests a blunted reaction to focal inflammation, although it may retain the ability to regenerate in the vicinity of ulcers.
Whenever possible, biopsy samples should be interpreted in conjunction with the clinical history. In patients with resolving colitis, the mucosa may feature reactive epithelial changes that linger after neutrophil infiltration of the mucosa has dissipated. Biopsy specimens from patients recently treated with intravenous cyclosporine may exhibit exaggerated reactive changes. (68)
Low-Grade Versus High-Grade Dysplasia
The histologic derangements that characterize dysplasia lie on a continuum. By convention, the distinction between LGD and HGD is based on the degree of preservation or loss of cellular polarity reflected by nuclear stratification. As a rule of thumb, LGD features nuclei that are confined to the basal half of the epithelial cells (Figure 3, A through F), whereas HGD is characterized by nuclei that are stratified randomly between the basal and apical halves (Figure 4, A through D).
The epithelium in LGD is simple columnar or cuboidal. Typically, the nuclei are crowded, elliptical, hyperchromatic, relatively uniform in size and orientation, and have smooth, delicate nuclear membranes, inconspicuous nucleoli, and typical mitotic figures. In most instances, goblet cells are inconspicuous or pleomorphic, but in some instances they may be hyperplastic or inverted (dystrophic), or the epithelium as a whole may consist of nongoblet mucinous cells, Paneth cells, or uniformly eosinophilic cells devoid of mucin vacuoles.
[FIGURE 2 OMITTED]
In HGD, the epithelium may be simple, stratified, or cribriform. The nuclei are haphazardly stratified or skewed, enlarged, pleomorphic, hyperchromatic, or vesicular and may contain prominent nucleoli or atypical mitotic figures. The cytoplasm is relatively undifferentiated and mucin vacuoles are inconspicuous or absent.
Lesions that contain both LGD and HGD may be classified as HGD unless the latter is a minor, focal component, in which case both components and their relative proportions are reported.
Indefinite for Dysplasia
A definitive diagnosis of dysplasia may be precluded either when the histologic features defy clear-cut distinction between reactive and dysplastic mucosa, as in some cases of severe inflammation and regeneration (Figure 5, A through D), or when the specimen is technically inadequate, for example, too small or superficial, misoriented, fragmented, or poorly fixed. Ambiguous changes may include reactive crypts with unusually stratified or basophilic nuclei, superficial villiform mucosa with inadequate sampling of the basal crypts, and hyperserrated, dilated crypts. In some cases, step sections of the tissue block offer a practical remedy, revealing diagnostically helpful details that were absent in the original slide.
[FIGURE 3 OMITTED]
[FIGURE 4 OMITTED]
The nature of any uncertainties should be conveyed in the pathology report. If the interpretation leans strongly in one direction or another, optional sub-classification as "probably positive" or "probably negative," as originally suggested by Riddell et al, (65) may be very helpful to the gastroenterologist in choosing among available management options.
Macroscopic Classification of Dysplasia
The clinical significance and management implications of dysplasia also depend on the corresponding macroscopic features. Dysplastic lesions may be classified broadly as raised or flat, depending on whether a corresponding lesion was observed by the endoscopist (Figure 6). Raised dysplastic lesions encompass a heterogeneous assortment of polyps, nodules, plaques, and excrescences, which may or may not be surrounded by flat dysplasia (Figure 7, A through F, and Table 1).
The most important determinant in managing patients with raised dysplastic lesions is whether the dysplasia is completely resectable by conventional snare endoscopy techniques. Nonresectability, whether by virtue of size, fixation to the colonic wall, or the presence of contiguous flat dysplasia, defines a group of lesions collectively referred to as dysplasia-associated lesion or mass (DALM). (69) These entities have been observed to harbor invasive cancer at colectomy in up to half of cases and are therefore an indication for immediate surgical management. This high cancer risk is independent of the histologic grade of dysplasia in preoperative biopsy specimens. (59,61,70,71)
Endoscopically resectable dysplastic lesions in IBD are generally of less concern and permit patients to be managed more conservatively. Dysplastic polyps that are either encountered in nondiseased areas of the colorectum, for example, proximal to the transition zone in UC, (32) or have a nondysplastic pedicle, (4,72-74) are considered to be sporadic adenomas unrelated to the colitis and are managed accordingly. Dysplastic polyps in colitic mucosa that are sessile and have distinct borders and a smooth, dome-shaped surface are referred to as adenoma-like dysplastic polyps. Follow-up studies after their endoscopic removal have reported no significant excess risk for the development of CRC. (60,75-78) This favorable outlook is maintained even when the resected polyps contain HGD. (78,79)
Determining whether a raised lesion is resectable endoscopically requires that the adjacent mucosa be biopsied to ensure that dysplasia does not extend microscopically beyond the visible boundaries of the polyp. In a study from St Mark's Hospital (60)--which included a group of 8 subjects with UC who underwent endoscopic polypectomy to remove 0.5-1.5 cm dysplastic polyps--3 subjects whose polyps were surrounded by microscopic flat dysplasia all developed CRC, whereas the 5 subjects with no adjoining flat dysplasia fared well. The endoscopic, histologic, and prognostic similarities between adenoma-like polyps in IBD and sporadic adenomatous polyps suggest that some, if not all, of the former are merely fortuitous adenomas, a conclusion that is also supported by limited molecular-based evidence. (80)
[FIGURE 5 OMITTED]
[FIGURE 6 OMITTED]
[FIGURE 7 OMITTED]
Nonetheless, it is recognized that reliance on endoscopic criteria to classify raised lesions is fraught with interobserver variation and difficult to apply in practice. (72) For example, a recent study (81) showed that IBD experts achieve greater accuracy than nonexpert endoscopists in academic or private practice settings. The use of ancillary techniques such as chromoendoscopy and confocal endoluminal microscopy may afford improvements in diagnosis. In fact, a recent British study with confocal microscopy (82) has claimed 97% accuracy in discriminating between DALMs and adenoma-like polyps.
Histologic comparisons of individual morphologic features in DALMs and adenoma-like dysplastic polyps have indicated that DALMs show increased architectural disarray, (83) villous architecture, and inflammation, (74) but these criteria have not been evaluated longitudinally and have so far lacked the statistical power to guide the management of patients with raised dysplasia. (74,83,84) However, polyps with "top-down" dysplasia, in which the dysplasia is confined to the upper crypts, are a favorable histologic marker when compared with polyps with full-thickness or "bottom-up" dysplasia (Figure 7, F). In a study (85) (published in abstract form) of 76 subjects with long-standing UC who were followed up after complete endoscopic polypectomy, the rate of progression to CRC was significantly lower among 37 patients with at least 1 top-down dysplastic polyp than among 39 patients with exclusively bottom-up dysplasia (P = .02) during a median follow-up period of 3 years; this rate was not statistically different from that of 349 patients without dysplasia during a mean follow-up interval of 7 years.
Additional longitudinal clinical studies and application of more sensitive molecular techniques are needed to better define the natural histories and pathogenesis of raised dysplastic lesions.
Flat dysplasia refers to dysplasia that is detected unexpectedly in random biopsies of mucosa without a corresponding macroscopic lesion, although occult dysplasia is a more suitable term considering that small or subtle raised lesions might easily go unnoticed in the inflammatory background of IBD. (86) Retrospective endoscopic studies have suggested that most dysplastic lesions are in fact endoscopically visible. On the basis of a review of random and targeted surveillance biopsies in 525 subjects with UC during a period of 15 years, Rutter et al (87) reported that 85 of 110 (77.3%) biopsy specimens of dysplasia or cancer corresponded to macroscopically visible lesions, whereas 25 (22.7%) were invisible. Similarly, on the basis of a review of surveillance biopsies in 46 subjects with UC during a period of 10 years, Rubin et al (88) reported that 38 of 65 dysplastic lesions (58.5%) and 8 of 10 cancers (80.0%) were visible as 23 polyps and masses, 1 stricture, and 22 mucosal irregularities. We have found that only some of the dysplastic lesions described as flat by endoscopists correspond to expanded mucosa resembling diminutive adenomatous polyps, whereas most correspond to histologically flat mucosa in which the crypts have been colonized by dysplastic epithelium, without alteration of the overall mucosal architecture.
Rubin et al (89) calculated that 64 endoscopic biopsies are required to detect the highest grade of flat dysplasia in a typical colon with 95% confidence. Sampling variations probably account for a high degree of inconsistency between serial endoscopic examinations and for cases in which patients have had advanced CRC despite negative examination results within the previous year. (41,59,90) Despite this, several studies90-92 have concluded that the number of biopsy samples obtained by gastroenterologists who perform surveillance, including IBD experts in academic settings, frequently falls short of the recommended guideline of 4 biopsy samples per 10 cm.
Recent technologic advances may help overcome some of these problems. Chromoendoscopy involving spray dying with indigo carmine or methylene blue, often combined with high-magnification endoscopy or confocal endoluminal microscopy, (93) has been shown to enhance the detection of occult dysplastic lesions, increase the yield of dysplastic lesions 3- to 6-fold as compared to conventional endoscopy, and reduce the number of biopsies needed to achieve equivalent results. (94-98) It remains to be seen whether current reliance on random biopsy sampling will eventually give way to surveillance protocols based on visually targeted biopsies as a means of achieving improved efficacy and reducing the proportion of negative specimens per examination.
Current US and European guidelines for implementation of endoscopic surveillance recommend that patients with extensive UC or colonic CD undergo initial screening colonoscopy beginning 8 to 10 years after the onset of colitis symptoms or immediately if there is concomitant sclerosing cholangitis. At least 4 random biopsy samples are to be taken every 10 cm throughout the colon, with additional biopsy specimens of any visible lesions of uncertain significance. (4,6,7) Subsequent surveillance examinations are to be performed at regular intervals of 1 to 2 years4 or 3 years (6,7) during the second decade, and possibly more frequently in later decades, in case the cancer hazard rate increases over time. (10) Biopsy specimens are to be interpreted by pathologists familiar with the criteria and nomenclature of the IBD Morphology Study Group (65) and findings that might significantly impact the course of management should be reviewed independently by a second pathologist. (4,5) Guidelines for the management of patients with dysplasia are summarized in Table 1 and discussed below.
The selection of appropriate endpoints for surgical intervention, when dysplasia is diagnosed, requires striking a balance between the risks of potentially unnecessary surgery and those of progression to incurable cancer if intervention is delayed. Two key considerations are the likelihood that a patient may be harboring undetected cancer at the time of examination and the likelihood that dysplasia, whether recognized or not, will evolve into cancer during a defined follow-up interval.
High-Grade Dysplasia and DALM
There is unanimous agreement in the literature that the detection of HGD or of a DALM with any degree of dysplasia carries a sufficiently high risk of concurrent CRC or short-term progression to CRC to warrant immediate colectomy barring unusual clinical circumstances. (4,5) An analysis of published results from 10 surveillance programs in 1994 reported that 10 of 24 (42%) patients with HGD and 17 of 40 (43%) patients with DALMs had CRC at immediate colectomy; after a follow-up period, 15 of 47 (32%) patients with HGD were diagnosed with CRC. (59) A 30-year summary of St Marks Hospital's surveillance program reported CRC in the colectomy specimens from 5 of 11 (45.5%) patients diagnosed with HGD and 30% to 33% who opted for immediate surgery; among 8 patients with HGD who opted for continued surveillance, 2 (25%) developed CRC. (61)
Flat Low-Grade Dysplasia
The optimal management of patients with flat LGD is controversial. Some authorities advocate continued or accelerated surveillance, some recommend immediate colectomy, and others recommend colectomy if the dysplasia is multifocal or is detected in serial examinations. The reported rates of progression from LGD to HGD or CRC among patients who opt for surveillance range from 3% to 10% after 10 years of follow-up, (99,100) 33% after 4 years, (61) and 53% to 54% after 5 years. (60,90) One of the latter studies90 reported equally high rates of progression whether the LGD was unifocal or multifocal. Some of the lower progression rates were based on diagnoses originally rendered before publication of the standardized classification system for dysplasia and without a separate category for equivocal biopsy specimens. Indeed, a 1994 St Marks study found that reclassification of its pre-1983 biopsy assessments by 2 pathologists led to a change in 5-year progression rates among patients with flat LGD from 16% to 54%. (60) In contrast, there has been near unanimity regarding the predictive value of flat LGD for CRC at immediate colectomy: 19% in a 1994 compilation of results from 10 surveillance studies, (59) 22% in a more recent meta-analysis of 20 surveillance programs including 11 new studies, (58) and 20% in a recent review of surveillance endoscopy results from St Marks Hospital. (61)
Low-grade dysplasia detected at an initial screening endoscopy (prevalent dysplasia) may carry a higher degree of risk than LGD detected during periodic surveillance (incident dysplasia), since the initial examination evaluates neoplastic changes accrued over a longer interval, but is subject to the same sampling error. (101,102)
Practice guidelines have recommended that patients with pathologically confirmed LGD who opt for continued surveillance instead of colectomy should undergo accelerated examinations until at least 2 examination results are negative. (6,7) However, it has also been observed that patients may present with advanced CRC after a preceding biopsy reveals LGD (90) and that once dysplasia has been diagnosed, dysplasia or CRC will usually be encountered in the future, despite multiple negative results from interim examinations. (90,101)
The rationale for aggressive management of patients with flat LGD has been reinforced by histologic evidence of potential direct progression from LGD to CRC, bypassing a stage of HGD (Figure 8). In a report from The Mount Sinai Hospital that describes 21 low-grade tubuloglandular adenocarcinomas, we observed that 92% arose directly from crypts with LGD or, in 1 case, IND. Although the cancers were low grade at the initial point of invasion, more than half evolved histologically into conventional and, in some cases, poorly differentiated carcinomas, in deeper regions of invasion. (47)
Indefinite for Dysplasia
Although there have been few longitudinal studies of patients with IBD and a biopsy diagnosis of IND, (103,104) there is evidence suggesting that they require closer follow-up than patients with negative biopsy results. A recent cohort study from The Mount Sinai Hospital103 compared the outcomes of patients with biopsy specimens reported as negative for dysplasia, IND, and flat LGD and reported 5-year progression rates to HGD or CRC of 1.1%, 9% and 45%, respectively. Because IND is a "wastebasket" category, accommodating biopsy specimens with a variety of interpretive and technical problems, the frequency of follow-up examinations needs to be individualized on the basis of all the available endoscopic and clinical information. It follows that even though published guidelines for surveillance recommend at least 1 repeated examination within 3 to 6 months, (4,105) there may be situations in which the degree of histologic, endoscopic, or clinical concern is high enough to warrant immediate reexamination and closer follow-up. Riddell et al (65) recommended that biopsy specimens classified as indefinite be subclassified formally as "probably positive" or "probably negative" if the pathologic interpretation leans in one direction or another. Besides assisting gastroenterologists in choosing among various management options, such as the scheduling of another examination, we have observed that these subclassifications correlate with the actuarial rates of progression to definite neoplasia over time (X. Gui, MD, PhD, and N.H., unpublished data, 2008).
[FIGURE 8 OMITTED]
Studies of interobserver variability in grading dysplasia have reported only fair performance by general and specialist gastrointestinal pathologists alike. As a rule, agreement levels are highest at the 2 extremes of the spectrum, that is, negative for dysplasia and HGD, and lowest for the middle categories, LGD and IND. (106-110) Studies assessing the performance of experts based on static (110) and dynamic (111) telepathology, both modalities that might improve access to expert consultative services, have yielded lower k values than with the use of corresponding glass slides.
MOLECULAR PATHOGENESIS: ETIOLOGIC AND RISK FACTORS
The distinctive pathogenetic characteristics of cancer development in IBD have attracted many studies seeking to identify corresponding etiologic and risk factors, molecular pathways and mechanisms, and markers that might be exploited for clinical purposes (Figure 9). Most of these studies have dealt with UC, and it remains to be seen how closely the shared features of colorectal neoplasia in UC and CD are mirrored at the molecular level.
Although the importance of genetic susceptibility in the development of IBD is irrefutable, its role as a risk factor for CRC in this population is not well defined. Several studies have reported that first-degree relatives of patients with IBD complicated by CRC are more than twice as likely as the general population to have CRC themselves; (35,112) however, a similar risk increment is observed in the families of patients with sporadic CRC. The relatives of patients with uncomplicated IBD face no significantly increased risk of developing CRC, (112-114) but conversely, a family history of sporadic CRC confers a doubling of the already increased rates of CRC among patients with UC. (35,36) Analogous findings have been reported in the cotton-top tamarin model of UC. (115) In summary, the risk for development of colitis-associated neoplasia may be influenced by heritable factors; however, these are not necessarily the same ones that predispose to sporadic CRC. For example, a mutation in the APC gene, which has been linked to the development of sporadic CRC in Ashkenazi Jewish patients, is not increased in frequency among patients with IBD. (116,117)
The etiologic role of inflammation in the pathogenesis of neoplasia in IBD is implied by the fact that disease duration, anatomic extent, and intensity of inflammation are among its principal risk factors. The interrelationships between chronic inflammation and cancer predisposition have emerged as a common theme in medicine, particularly in the gastrointestinal tract, but the specific molecular signals that mediate them in IBD are only now beginning to be elucidated.
Research based mostly on murine colitis models or human colon cancer cell lines suggests that various inflammatory mediators are active participants in tumor promotion and progression. The proinflammatory cytokines TNF-[alpha] (tumor necrosis factor [alpha]), IL-6, and IL-23 have each been implicated in the interplay between inflammatory and intestinal epithelial cells during IBD-associated carcinogenesis. (118-123) For example, transforming growth factor [beta]-dependent IL-6 transsignaling, derived from tumor-infiltrating T cells, has been implicated in tumor progression in the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse colitis model. (124) Intraluminal bacterial endotoxins, TNF-[alpha], and other proinflammatory cytokines act through extracellular receptors such as Toll-like receptors to initiate phosphorylation cascades that transmit signals to key transcription factors such as nuclear factor (NF) [kappa]B. (125-127) Toll-like receptor 4, which responds specifically to bacterial lipopolysaccharide ligand and is expressed at low levels in normal intestinal mucosa, was shown to be upregulated in the mucosa of patients with IBD, in UC-associated CRC, and in colon tumors that develop in the AOM/DSS mouse model. (128) Conversely, toll-like receptor 4-deficient mice developed fewer and smaller tumors and produced reduced levels of cyclooxygenase2 expression and prostaglandin [E.sub.2] production, both of which are mediators of colorectal tumorigenesis. Mice deficient in cytoplasmic Nod1, another innate immune receptor that signals through NF-[kappa]B, were reported to develop more severe colitis and a greater tumor burden when exposed to AOM/DSS than controls. (129) Interestingly, prior depletion of the gut microbial flora abrogated these effects, echoing an earlier study in which intestinal microflora were essential for the induction of inflammation-dependent carcinogenesis in transforming growth factor [beta]1-deficient mice. (130) The link between colitis and tumor progression was reinforced by a study (131) reporting that deletion of IKK[beta], the major positive regulator of NF-[kappa]B, in murine intestinal epithelial cells, resulted in decreased tumor incidence, but not tumor size, in AOM/DSS-treated mice. This decrease was attributable to increased apoptosis during tumor promotion despite no decrease in inflammation. However, the same deletion in myeloid cells resulted in decreased tumor size through diminished expression of proinflammatory cytokines, implicating the latter as tumor growth factors. (131) Conversely, deletion of CYLD, a deubiquitinating enzyme that functions to down-regulate NF-[kappa]B, resulted in more severe colonic inflammation and increased incidence of colonic adenocarcinomas. (132)
[FIGURE 9 OMITTED]
Among the implications of these studies is the realization that links exist between commensal bacterial components and elements of the innate immune response and inflammation-induced tumorigenesis; (133) and that corresponding mechanisms, important for the initiation and maintenance of both chronic inflammation and tumor progression, involve NF-[kappa]B-regulated factors such as cytokines and chemokines, proangiogenic and antiapoptotic factors, and matrix proteases.
The mechanisms by which inflammatory cytokines promote the epithelial DNA mutations necessary for the initiation of neoplasia remain largely undefined. A potential clue has recently emerged from a study of activation-induced cytidine deaminase (AID), an enzyme that under physiologic conditions regulates class switch recombination and somatic hypermutation in immunoglobulin genes of activated B cells. The study demonstrated that AID induction by proinflammatory cytokines in human colon cancer cell lines could lead to the accumulation of TP53 mutations. (134) The deaminase was over-expressed in both dysplastic and nondysplastic colonic epithelium from patients with UC and CD, as well as in some sporadic colon cancer specimens. Other mechanisms of this type may account for the production of potentially carcinogenic mutations in colonic epithelial cells under the control of proinflammatory cytokines.
The innate immune system may also provide a microenvironment that permits or even promotes tumor progression in states of chronic inflammation. For example, IL-23, a proinflammatory cytokine that promotes the Th17 T-cell differentiation pathway and plays an important role in the pathogenesis of IBD, (135) is upregulated in some human tumors, whereas its deletion leads to increased infiltration of cytotoxic T cells and growth restriction of transformed or transplanted tumors. (136) It is likely that other tumor cell products are capable of recruiting and activating inflammatory cells capable of enhancing or limiting tumor growth. Unraveling the complex relationships between tumor cells, their microenvironment, and the roles of cytokines within it may afford future targets for chemoprophylaxis.
Oxidative stress and the generation of reactive oxygen species by inflammatory cells are thought to contribute to the development of dysplasia and CRC in the setting of IBD. (137,138 For example, colonic tissue and plasma from patients with IBD contain significantly higher levels of the premutagenic DNA adduct 8-hydroxydeoxyguanosine--a product of reaction with hydroxyl radicals--than do controls. (139-141) In 1 study, these levels correlated with longer duration of disease and endoscopic or histologic activity. (140) Mitochondrial DNA, which is relatively sensitive to reactive oxygen species, contained an increased burden of mutations in patients with UC and an even higher burden in those with colitis-associated CRC. (139) The proinflammatory cytokine TNF-[alpha] was recently shown to cause genetic alterations and cellular transformation in cultured cells, both of which could be inhibited by antioxidants. (142)
In the iron-enhanced DSS-induced mouse model of colitis-associated tumorigenesis, treatment with inositol compounds reduced tumor burden by modulating nitro-oxidative stress. Deletion of the DNA repair enzyme Ogg1, which recognizes and excises these modified bases, resulted in increased tumor incidence and volume. (143,144) By the same token, increased levels of long chain n-3 polyunsaturated fatty acids in transgenic mice treated with AOM/DSS resulted in decreased colonic inflammation, reduction in tumor number and size, and, importantly, lower activity of NF-[kappa]B. Therefore, a protective effect exerted by antioxidant dietary compounds may have important implications for diet-based prophylaxis in IBD. (145,146)
MOLECULAR PATHOGENESIS: MECHANISMS AND PATHWAYS OF CARCINOGENESIS
Despite the distinct origins and pathologic characteristics of IBD-associated and sporadic colorectal neoplasia, their molecular pathogenesis shares certain basic mechanisms. (62,147,148) Both depend on genomic instability for the development of mutations leading to CRC and both generally exhibit either chromosomal or microsatellite instability in a mutually exclusive manner, with relative frequencies of approximately 85% and 15%, respectively. (149-151)
Chromosomal instability (CIN) is manifested by genomic alterations that affect large DNA segments, resulting in aneuploidy, translocations, deletions, and gene copy amplifications. The extent and types of CIN associated with IBD-related dysplasia and CRC have been evaluated by comparative genomic hybridization, fluorescent in situ hybridization (FISH), flow cytometry, and DNA fingerprinting. Chromosomal instability in IBD, in addition to its similar frequency to CIN in sporadic carcinogenesis, also affects many of the same loci and results in similar mean numbers of chromosomal alterations per case. (149,152) An important distinction, however, is that CIN in UC is distributed broadly, involving even mucosa that is negative for and remote from dysplasia, whereas in sporadic CRC it is restricted to tumor tissues. (149,153-155) Chromosomal alterations therefore appear to occur early in the course of IBD-related neoplastic progression and in advance of the histologic features of dysplasia.
Chromosomal instability is typically absent in patients with UC who do not also harbor dysplasia or CRC. Thus, the presence or absence of CIN in nondysplastic mucosa has been advanced as a marker enabling patients to be stratified into distinct categories of progressors and nonprogressors, respectively. (149,154,156-158) Progressors may be characterized by early onset and longer duration of disease. (159) Recently, FISH-based detection of combined alterations in 4 key chromosomes in nondysplastic mucosa was reported to be 100% sensitive and 92% specific in distinguishing progressors from non-progressors, suggesting the application of such methods to improve surveillance. (160)
One proposed mechanism by which chronic inflammation could lead to CIN involves accelerated telomere shortening. Colonic epithelial cells from patients with UC have been shown to contain shorter telomeres than those from healthy control subjects. This difference is attributable to more rapid cell turnover, increased replication, and increased oxidative damage resulting from repeated cycles of injury and regeneration. (161,162) Telomere shortening is correlated in turn with CIN, as reflected by higher rates of chromosomal arm and centromere loss and higher frequency of anaphase bridges in the colonic epithelium of patients with UC who have dysplasia or cancer, as opposed to nonneoplastic controls. (158) Telomere shortening beyond a critical point is associated with aging as well as growth arrest, through replicative senescence when DNA damage checkpoints are intact, but with chromosomal damage, such as breaks and end-to-end fusions, when these checkpoints are defective. (163,164) Thus, telomere shortening could facilitate CIN, provided that DNA damage checkpoints are somehow also inactivated through mutations of checkpoint genes like TP53. The rates of telomere shortening observed in patients with UC are double those seen in healthy patients and occur mostly during the first 8 years of disease, the time frame when the risk of CRC begins to become clinically significant. (162)
Defective DNA mismatch repair manifested by microsatellite instability (MSI) has been implicated in IBD-associated carcinogenesis. It occurs at approximately the same frequency as in sporadic CRC, that is, approximately 15% to 20% of cases, (151,165-169) although both lower (170-172) and higher rates (173-178) have been reported, typically in studies with small subject populations. Interestingly, 5 of 6 studies that observed MSI in more than 40% of their IBD-associated tumor samples were based on Japanese subjects, a fact suggesting that ethnic or local environmental factors may influence the rates of MSI in the setting of IBD.
A common finding among these studies is that the rates and levels of MSI do not always correlate with more advanced histologic features. (169,170) Many instances of higher grades of dysplasia or CRC have featured lower rates of MSI than less advanced lesions, (168,173,175,177,178) as well as lower numbers of affected loci. (149,169) Some authors (170) have drawn the conclusion that MSI occurs early in the progression of dysplasia to carcinoma.
It is difficult as yet to draw conclusions regarding the pathogenetic significance of MSI during early stages of carcinogenesis in IBD. Many studies have reported MSI in regenerative, nondysplastic, and indefinite mucosa in patients with long-standing UC, albeit with higher (167,172,175,178) or lower frequencies (168,173,174,177) relative to dysplastic and cancer tissues. However, 3 larger studies (150,171,179) have failed to demonstrate any signs of MSI in nondysplastic samples. Most studies have not specified the duration, severity, or extent of colitis, and attempts to correlate MSI with disease duration have yielded results that are either discordant or not statistically significant. (173,175,178)
Current evidence indicates that MSI in IBD-associated CRC is a result of acquired rather than inherited mutations of DNA mismatch repair genes. It has been suggested that DNA damage associated with inflammation may exert a selective pressure on cells in which the corresponding enzymes are defective. For example, MSH2-null mice developed dysplasia and carcinoma at significantly higher rates than heterozygotes or controls after exposure to DSS; most had high levels of MSI. Importantly, MSI was also detected in the surrounding nondysplastic tissue. (180)
Alternatively, MSI in nondysplastic epithelium may reflect a temporary state of hypermutation resulting from sustained levels of oxidative stress that eventually overwhelm the capacity of the cellular machinery to repair damage caused by reactive oxygen species. (147,178) This theory would account for relatively low levels and small numbers of affected loci observed in some studies of IBD. (167,169,172,177) It would follow that environmental and dietary factors might affect the dynamic balance between oxidative DNA damage and enzymatic repair and account for MSI in some cases of IBD. One study (181) indeed reported low serum, blood, and colonic levels of folate in patients with IBD whose nondysplastic colonic mucosa showed MSI and noted a change in the MSI pattern after dietary folate supplementation.
Aberrant DNA Methylation
The epigenetic phenomenon of gene silencing due to widespread DNA hypermethylation of promoter regions at CpG (cytosine-guanine) islands, or CpG island methylator phenotype, has been implicated in the control of various tumor suppressor genes in what is considered an early and important step in carcinogenesis. Early studies in tissues from patients with UC have shown that, similarly to sporadic CRC, tumor suppressor genes and negative cell cycle regulators such as [p14.sup.ARF], [p16.sup.INK4a], and genes in the WNT signaling pathway, are frequently hypermethylated. (182-185) Hypermethylation was observed in dysplastic lesions, in carcinomas, and in corresponding nonneoplastic samples but not in noncolitic controls, suggesting that these are early events in UC-related carcinogenesis and supporting the concept of widespread field defects in the colonic epithelium of patients with IBD.
Certain genes that were hypermethylated in sporadic CRC, such as E-cadherin, eyes absent 4 (EYA4), and HPP1, also exhibited increased CpG island methylation in colitis-associated dysplasia but not in nondysplastic mucosa, suggesting a degree of overlap between the respective mechanisms of carcinogenesis and identifying them as potential candidates for new diagnostic markers for dysplasia. (186-189) Other genes such as estrogen receptor gene (ER), which are also methylated in sporadic CRC, showed higher rates of and more extensive methylation in nonneoplastic samples from patients with UC who had neoplastic lesions elsewhere in their colon than in samples from patients with UC who did not have neoplasia; this observation possibly supports the dichotomy between progressors and nonprogressors and hints at corresponding molecular mechanisms. (190,191)
Hypermethylation and silencing of genes that encode DNA repair enzymes such as MLH1 and MGMT ([O.sup.6]-methylguanine-DNA methyltransferase) has been identified in IBD-related dysplasia and CRC but not in nonneoplastic mucosa. (166,173,192) In the case of MLH1, hypermethylation was significantly associated with high levels of MSI. An earlier study (193) had reported that 4 genes that are affected by age-related methylation, ER, MYOD, CDKN2A exon 1, and CSPG2, are highly methylated in dysplastic colonic epithelium and that hypermethylation of 3 of these genes also occurred in the nondysplastic epithelium of patients with UC who had dysplasia or CRC elsewhere in their colon. Some have viewed these findings as evidence that the increased risk of CRC in IBD may reflect a process akin to premature aging of the colonic mucosa. (162) However, it has also been reported that fully developed CRC, as opposed to dysplasia, exhibits lower levels of methylation than sporadic CRC. (194) This could mean that, although hypermethylation events may play a role in the development of dysplasia in IBD, the process of progression to cancer bypasses this step or occurs more rapidly when other mechanisms (eg, CIN) are dominant. In a study using glutathione peroxidase-deficient mice, (195) genes targeted by inflammation-dependent methylation were distinct from those targeted by age-dependent methylation, suggesting that aberrant methylation may be more than an aging phenomenon.
Although certain tumor-related molecular alterations can be identified in the nondysplastic mucosa of a subset of patients with IBD, clonal expansion is a necessary condition for clinically relevant neoplastic progression to occur. DNA fingerprinting studies, performed on micro-dissected crypt epithelium of patients with UC who had dysplasia or CRC, have reported significant molecular aberrations in up to 20% of target sites, almost half of which were clonally expanded. (196) Recently, crypt epithelial cells, obtained by laser capture microdissection from patients with UC who had dysplasia/carcinoma, were analyzed by polymerase chain reaction-based sequencing for specific oncogenic mutations. (197) In most cases, a specific monoclonal mutation (mostly in TP53, but also in K-ras) was identified in all crypts across a lesion and even in some surrounding nondysplastic crypts. Furthermore, in these patients, significant clonal expansion of p53 and K-ras mutations were observed in large segments of the colon (3-14 cm), spanning phenotypically heterogeneous epithelium including nondysplastic and dysplastic crypts. At least a subset of early clonal lesions may be identifiable endoscopically; a recent report198 has found that, as in sporadic CRC, aberrant crypt foci are significantly increased in parallel with dysplasia and CRC and frequently harbor p53 mutations and p16 hypermethylation.
Table 2 lists some of the key gene targets associated with colorectal neoplasia in IBD.
CLINICAL APPLICATIONS OF MOLECULAR MARKERS
In addition to technologic advances in the practice of endoscopy, there have been limited attempts to improve on the current practice of surveillance by using some of the molecular markers that play a role in IBD-related carcinogenesis. The fact that neoplastic colonic epithelial cells exfoliate into the lumen more readily than those from normal mucosa has been exploited in the development of noninvasive methods to detect tumor-related molecular markers, for example, DNA mutations in stool (199,200) and in colonic lavage fluid. (201-203) The feasibility of stool-based testing in IBD was initially demonstrated by detection of K-ras mutations in DNA derived from stool in a small cohort of patients with UC and CD, especially those with active disease. (204) Results based on multiple target mutations (eg, K-ras, TP53, and APC) in fecal DNA from an average-risk population were more sensitive than, and equally specific to, fecal occult blood testing with respect to the detection of invasive carcinoma and advanced neoplasia. (205) Further technologic innovations in the detection of mutated DNA from stool promise to transform the way cancer screening is performed, initially in the general population, (206,207) and eventually in patients with IBD.
Diagnosis of Dysplasia
As the molecular pathogenesis of dysplasia is unraveled, so does the potential increase for the discovery of new immunohistochemical markers as diagnostic aids. The markers studied thus far fall mainly into the categories of tumor-associated antigens (eg, sialyl-Tn), (208,209) markers of altered cell proliferation or apoptosis (eg, Ki-67, bcl-2, survivin, YB-1, topoisomerase II[alpha]), (210-213) and intercellular adhesion molecules (eg, [beta]-catenin, E-cadherin) and tumor suppressors (eg, p53, p21). (215-217) The proliferation marker Ki-67, which ordinarily stains replicative basal colonocytes, exhibits an abnormal surface staining pattern in most dysplastic lesions, as does topoisomerase II[alpha]. (210,213) p53 overexpression, which has been studied extensively, correlates only partly with the presence of mutations and is sometimes detectable in inflamed but nondysplastic mucosa. (218,219) The enzyme [alpha]-methylacyl coenzyme A racemase, especially in combination with p53, has afforded good sensitivity and specificity in small series. (220,221) Finally, a combination of techniques for the detection of chromosomal alterations (FISH, analysis of telomere length and anaphase bridging) in endoscopic biopsies achieved a sensitivity and specificity greater than 90% in identifying individuals at risk for progression to dysplasia. (160) Larger longitudinal studies will be required to enable these and any emerging markers to meet the standards of validation required for application in clinical practice.
Colorectal cancer, the most lethal long-term complication of IBD, is the culmination of a complex sequence of molecular and histologic derangements of the intestinal epithelium that are initiated and at least partially sustained by chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is underway and serving as an endpoint in colonoscopic surveillance of patients at high risk for CRC. The diagnosis and grading of dysplasia in endoscopic surveillance biopsies plays a decisive role in the management of patients with IBD. Although interpathologist variation, endoscopic sampling problems, and incomplete information regarding the natural history of dysplastic lesions are important limiting factors, indirect evidence that surveillance may be an effective means of reducing cancer-related mortality in the population with IBD has helped validate the histologic criteria, nomenclature, and clinical recommendations that are the basis of current practice among pathologists and clinicians. Emerging technologic advances in endoscopy promise to make surveillance more effective, but ultimately, the greatest promise for cancer prevention in IBD lies in expanding our thus far limited understanding of the molecular pathogenetic relationships between neoplasia and chronic inflammation.
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Noam Harpaz, MD, PhD; Alexandros D. Polydorides, MD, PhD
Accepted for publication July 10, 2009.
From the Departments of Pathology (Drs Harpaz and Polydorides) and Medicine (Dr Harpaz), The Mount Sinai School of Medicine, New York, New York.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Noam Harpaz, MD, PhD, Department of Pathology, The Mount Sinai School of Medicine, Annenberg 15-40A, One Gustave L. Levy Pl, New York, NY 10092 (e-mail: Noam.firstname.lastname@example.org).
Table 1. Classification and Management of Dysplasia in Patients With Inflammatory Bowel Diseasea Diagnosis Surroundings Endoscopic Features Negative for Normal or None noted dysplasia colitis Indefinite for Colitis Variable dysplasia Sporadic Normal Conventional adenoma features of sessile or pedunculated adenoma Colitis Conventional features of pedunculated adenoma Adenoma-like Colitis Sessile, dysplastic endoscopically polyp resectable, dome-shaped, sharp boundaries, no gross stigmata of cancer DALM Colitis Nonresectable by polypectomy, poorly defined boundaries or stigmata of cancer Flat LGD Colitis None noted by endoscopist Flat HGD Colitis None noted by endoscopist Associated Diagnosis Precautions Cancer Risk Negative for NA Low (5-y rate: 1.1% dysplasia for progression to HGD or CRC) (103) Indefinite for NA Intermediate (5-y dysplasia rate: 9% for progression to HGD or CRC) (103) Sporadic 1. Absence of Low (76-79) adenoma surrounding colitis should be confirmed microscopically 2. Caution if pedicle is dysplastic 3. Caution if patient is <40 y or lesion recurs after polypectomy No dysplasia along Low (74) pedicle Adenoma-like 1. No flat Low (76-78) dysplastic dysplasia in polyp adjacent mucosa or elsewhere in colon (2.) Caution if patient is <40 y or lesion recurs after polypectomy 3. Presence of HGD need not alter management (78,79) DALM Confirm diagnosis >40% risk of cancer with second at colectomy pathologist (59,70) Flat LGD 1. Confirm 20% risk of cancer diagnosis with at colectomy second pathologist (58,59,61); ~50% progression to 2. Unifocal LGD had cancer or HGD in 5 similar risk to years according to multifocal LGD in 1 some studies study (90) (60,90) Flat HGD Confirm diagnosis >40% risk of cancer with second at colectomy; pathologist 25%-32% progression to cancer in 5 years if colectomy is deffered (59,61) Recommended Diagnosis Management Negative for Maintain dysplasia surveillance Indefinite for Repeat dysplasia examination immediately or within 6 months (see text); consider accelerated surveillance Sporadic Polypectomy, adenoma maintain surveillance Polypectomy, maintain surveillance Adenoma-like Short-term dysplastic follow-up polyp examination, maintain surveillance DALM Colectomy Flat LGD Colectomy (alternatively, accelerated surveillance; see text) Flat HGD Colectomy Abbreviations: CRC, colorectal cancer; DALM, dysplasia-associated lesion or mass; HGD, high-grade dysplasia; LGD, low-grade dysplasia. (a) Adapted from Harpaz (71) with permission from Elsevier, copyright 2007. Table 2. Gene Targets Associated With Colorectal Neoplasia in Inflammatory Bowel Disease Gene Prevalence (Chromosomal in IBD- Locus Studied) Function Related CRC APC (5q21) Tumor suppressor Rare (>15%) gene (cell adhesion) DCC/DPC4 Tumor suppressor Common (18q21) gene (cell (.50%) adhesion) TP53 (17p13) Tumor suppressor Common gene (cell cycle, (.50%) apoptosis) CDKN2A Tumor suppressor Frequent (9p21) gene (cell cycle inhibitor) CDKN2A Tumor suppressor Frequent (9p21) gene (indirect p53 regulator) CDKN1B Tumor suppressor Under- (12p13) gene (cell cycle expressed regulation) in CRC E-cadherin Tumor suppressor Frequent gene (cell adhesion) K-ras (12p12) Oncogene (cell cycle Uncommon regulation) (,25%) c-src Oncogene Intermediate TGFBR2 RII TGF-b1 receptor MSI-related gene CRC (less common than sporadic MSI CRC) MSH2 (2p22) DNA mismatch MSI-related repair gene CRC MLH1 DNA mismatch MSI-related repair gene CRC (less common than sporadic MSI CRC) Gene Timing in the Pathogenesis or (Chromosomal Dysplasia-Cancer Mechanisms of Locus Studied) Sequence Mutation APC (5q21) Late HGD, CRC DCC/DPC4 Early Dysplasia (18q21) TP53 (17p13) Early May precede dysplasia CDKN2A Early Hypermethylation (9p21) CDKN2A Early Hypermethylation (9p21) CDKN1B (12p13) E-cadherin Early Hypermethylation K-ras (12p12) Late HGD, CRC c-src Unknown LGD to HGD TGFBR2 RII Unknown MSI MSH2 (2p22) Unknown MSI MLH1 Unknown MSI, hyper- methylation Gene (Chromosomal Locus Studied) Source, y APC (5q21) Willenbucher et al, (149) 1999; Maia et al, (150) 2005; Aust et al, (152) 2000 Willenbucher et al, (153) 1997; Umetani et al, (176) 1999; Aust et al, (222) 2002; Tarmin et al, (223) 1995; Redston et al, (224) 1995; Greenwald et al, (225) 1992; Tomlinson et al, (226) 1998; Kern et al, (227) 1994; Aust et al, (228) 2001 DCC/DPC4 Willenbucher et al, (149) 1999; (18q21) Aust et al, (152) 2000; Willenbucher et al, (153) 1997; Tomlinson et al, (226) 1998; Hoque et al, (229) 1997; Lei et al, (230) 1996 TP53 (17p13) Maia et al, (150) 2005; Aust et al, (152) 2000; Rabinovitch et al, (154) 1999; Wong et al, (212) 2000; Harpaz N et al, (216) 1994; Hussain et al, (218) 2000; Holzmann et al, (219) 1998; Greenwald et al, (225) 1992; Brentnall et al, (231) 1994; Burmer et al, (232) 1992; Chaubert et al, (233) 1994; Klump et al, (234) 1997; Nathanson et al, (235) 2008; Yin et al, (236) 1993 CDKN2A Hsieh et al, (182) 1998; Issa et al, (193) (9p21) 2001 CDKN2A Moriyama et al, (183) 2007; (9p21) Sato et al, (184) 2002 CDKN1B Walsh et al, (237) 1999 (12p13) E-cadherin Azarschab et al, (186) 2002; Wheeler et al, (187) 2001; Tomlinson et al, (226) 1998; Ilyas et al, (238) 1997; van Dekken (239) et al, 2007 K-ras (12p12) Lyda et al, (172) 2000; Umetani et al, (176) 1999; Redston et al, (224) 1995; Chaubert et al, (233) 1994; Holzmann et al, (240) 2001; Burmer et al, (241) 1990; Meltzer et al, (242) 1990; Bell et al, (243) 1991; Aust et al, (244) 2005 c-src Cartwright et al, (245) 1994 TGFBR2 RII Souza et al, (246) 1997 MSH2 (2p22) Noffsinger et al, (168) 1999; Brentnall et al, (247) 1995 MLH1 Fleisher et al, (166) 2000 Abbreviations: APC, adenomatous polyposis coli; CRC, colorectal carcinoma; DCC, deleted in colon cancer; HGD, high-grade dysplasia; LGD, low-grade dysplasia; MSI, microsatellite instability; TGF, transforming growth factor.
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