—  SHORT COURSE  —

A PRACTICAL APPROACH TO GASTROINTESTINAL PATHOLOGY


ULCERATIVE COLITIS, DYSPLASIA AND CARCINOMA

John R. Goldblum, M.D.





Case 5 - Chronic Ulcerative Colitis - High Grade Epithelial Dysplasia
Case 5 - Chronic Ulcerative Colitis - High Grade Epithelial Dysplasia
Case 5 - Chronic Ulcerative Colitis - High Grade Epithelial Dysplasia

It is well known that patients with ulcerative colitis (UC) are at an increased risk of developing dysplasia and carcinoma, although the exact magnitude of this risk is unknown. Various studies that have investigated this problem have suffered from small numbers of patients, relatively short follow-up intervals and referral center bias.1,2 Patients who are at highest risk include those with extensive colitis (proximal to the splenic flexure), those with disease duration of greater than ten years and those with primary sclerosing cholangitis.3-6 Some have also suggested that an early age of onset of colitis increases this risk.7 Patients with severe symptoms of colitis (fulminant colitis) will often have a colectomy before their risk of dysplasia/cancer is significantly increased, and thus patients who are at highest risk are often those with long-standing well-controlled asymptomatic disease. Currently, most gastroenterologists enroll their patients with long-standing extensive colitis into colonoscopic surveillance programs to detect dysplasia or at worst, an early-stage curable carcinoma. Although the benefits of such a program are controversial (discussed below), it is important to understand the concept of dysplasia, how to recognize it histologically, and understand the pitfalls of using dysplasia as a marker of increased cancer risk.

Dysplasia: A Marker and Precursor of Carcinoma
Dysplasia is an unequivocal neoplastic change that is intraepithelial and confined by the basement membrane surrounding the gland within which it arises. The observation that dysplasia is often seen adjacent to an invasive carcinoma is supportive evidence that this lesion is a precursor to the invasive stage.8,9 An important issue that must be resolved is how often dysplasia is seen distant from a carcinoma, as this would be useful in determining its utility as a marker of carcinoma. Connell et al found dysplasia distant to a carcinoma in 37 of 50 (74%) proctocolectomy specimens, with an average of 27 blocks evaluated.9 Similar results were obtained by Ransohoff et al10 and Taylor et al.11 In our review of resection specimens with adenocarcinoma arising in UC from the Cleveland Clinic Foundation,12 dysplasia was found in mucosa distant to the carcinoma in 92% of cases, including 76% and 85% with low-grade and high-grade dysplasia, respectively. When compared to a control group of 100 sporadic colorectal carcinomas, UC-related carcinomas were significantly more likely to arise in younger patients, arise in the right colon, to be non-intestinal type, poorly differentiated and higher Dukes' stage.

The Histologic Recognition of Dysplasia
The recognition of dysplasia can be extremely challenging, particularly in biopsy specimens with active disease, as it can be difficult or impossible to separate reparative from true dysplastic changes. In an attempt to standardize the nomenclature and criteria for dysplasia, the Inflammatory Bowel Disease-Dysplasia Morphology Study Group proposed a three-tiered classification scheme for the evaluation of dysplasia in biopsy specimens from patients with inflammatory bowel disease including 1) negative for dysplasia; 2) positive for dysplasia, either low-grade or high-grade, and 3) changes indefinite for dysplasia.13

In my opinion, the low-magnification evaluation of a biopsy specimen is probably the most useful way to recognize the presence or absence of dysplasia, as true dysplastic changes are typically recognizable at low magnification. Most dysplastic lesions in UC resemble adenomas seen in non-colitic patients and are therefore easily recognizable. Other dysplastic lesions do not resemble adenomas, but more closely resemble the form of dysplasia seen in Barrett's esophagus.8 In low-grade dysplasia, there is nuclear crowding, often with some stratification of nuclei, nuclear pleomorphism and probably most important, nuclear hyperchromasia. The glandular architecture is usually not markedly abnormal. The distinction between low-grade and high-grade dysplasia is made on the degree of cytologic abnormality that is present, with more marked nuclear pleomorphism, hyperchromasia and stratification seen in high-grade dysplasia. In many cases, high-grade dysplastic lesions will be accompanied by marked architectural abnormalities, often with a villiform surface. Certainly in some cases, the distinction between low-grade and high-grade dysplasia is somewhat arbitrary.

A chronic colitis that is active can show marked reparative changes that may be difficult or impossible to separate from true dysplasia. Under such circumstances, a diagnosis of indefinite for dysplasia is warranted. Although the Inflammatory Bowel Disease-Dysplasia Morphology Study Group subdivides indefinite for dysplasia into three subcategories (probably inflammatory, probably dysplastic, and unknown), we do not subgroup the indefinite category at the Cleveland Clinic Foundation, although we do attempt to offer an explanation in a comment as to why we believe the biopsy is indefinite for dysplasia. Although it is certainly possible to make a diagnosis of dysplasia in an active colitis, one must be cautious in this situation, particularly when there is an absence of cytologic atypia on the surface epithelium.

Sporadic adenoma versus IBD-Associated Dysplasia (Polypoid Dysplasia)
Given the frequency of sporadic adenomas, it is not surprising that adenomas can also arise in patients with UC. However, as previously mentioned, since most IBD-associated dysplasias resemble sporadic adenomas, there is no way to reliably distinguish these lesions histologically. The risk of synchronous or metachronous invasive carcinoma differs markedly in these two settings, as patients with IBD- associated dysplasia have a much greater risk of having or developing carcinoma.14 One can be confident that one is dealing with a sporadic adenoma if it occurs in an area not affected by IBD (for example, a right-sided adenoma in a patient with left-sided colitis). However, if the adenoma-like dysplastic lesion arises within an area involved by IBD, then this problem becomes much more difficult. In an attempt to distinguish sporadic adenomas from adenoma-like dysplastic lesions arising in IBD, studies have evaluated whether histologic features, molecular genetic features or the location of the lesion in question relative to the inflammatory bowel disease can be used to reliably distinguish between these lesions.

In 1993, Schneider and Stolte proposed histologic criteria that would allow for the separation of sporadic adenomas from IBD-related dysplastic lesions.15 However, this separation was based on predetermined, somewhat arbitrary criteria, and follow-up data was not provided. Although the morphologic observations that these authors made may be valid, follow-up information in this cohort would be most useful to validate their observations.

In 1998, Torres et al16 attempted to evaluate this problem in another way. They evaluated 89 polypoid adenomatous lesions from 59 patients with IBD, including 51 patients with UC and 8 patients with Crohn's disease, and correlated the morphologic features of these adenoma-like lesions with clinical, endoscopic and follow-up data. Lesions were classified as probable sporadic adenomas if the lesion was not located within an area of histologically proven colitis. A lesion was classified as a probable IBD-associated dysplastic lesion if it developed within an area of colitis and there was associated flat dysplasia or adenocarcinoma that was detected during follow-up evaluation. Finally, lesions were classified as indeterminate type if they arose in an area involved by IBD, but neither flat dysplasia nor adenocarcinoma was detected within the follow-up evaluation. Of the patients with probable sporadic adenomas, follow-up information was available in nine of these patients, and none developed subsequent dysplasia or adenocarcinoma. In contrast, of the 31 patients with either indeterminate polyps or probable IBD-associated dysplastic lesions with follow-up information, 13 patients either had or developed flat dysplastic lesions or adenocarcinoma in adjacent mucosa (including five patients with probable IBD-associated dysplastic lesions who had flat dysplasia in adjacent mucosa at the onset). Using these categories, patients with probable IBD-associated dysplastic lesions were younger (median age 48 years) when compared to those with probable sporadic adenomas (median age 63.5 years), were more likely to have active disease (85% vs. 50%) and were more likely to have a longer duration of disease (median 11 years vs. 5 years). Histologically, patients with probable IBD-associated dysplastic lesions more commonly had lamina propria mononuclear inflammation (60% vs. 16%), lamina propria neutrophilia (60% vs. 36%) and most importantly, were significantly more likely to have an admixture of dysplastic and non-dysplastic crypts on the surface of the polyp (60% vs. 16%).

In summary, although several studies have attempted to distinguish between sporadic adenomas and adenoma-like IBD-associated dysplastic lesions, in my opinion, these lesions cannot be distinguished on histologic grounds alone. More recently, there has been a trend to evaluate molecular biologic markers that might be useful in distinguishing between IBD-related dysplastic lesions and sporadic adenomas. Several recent studies suggest that the adenomatous polyposis coli (APC) gene is less significant in the dysplasia-carcinoma sequence of UC when compared to sporadic colorectal carcinomas.17-19 For example, Fogt et al. found loss of heterozygosity of the APC gene (on 5q) in 4 of 19 (21%) patients with sporadic adenomas, when compared to none of 15 cases of IBD-related high grade dysplasia without associated carcinoma.19 Furthermore, loss of heterozygosity of p16 (on 9p21) was found in 7 of 14 (50%) patients with IBD-related high grade dysplasia without associated carcinoma, compared to only 1 of 22 (4.5%) patients with sporadic adenomas. More recently, Fogt et al20 found loss of heterozygosity at the von Hippel Lindau gene locus (on 3p25) in 35% of either flat or polypoid dysplastic lesions arising in UC, whereas none of the adenomas tested had loss of heterozygosity at this locus. Studies by Mueller et al 21 and Walsh et al 22 have evaluated the utility of immunohistochemical markers for p53, bcl-2 and b catenin in distinguishing between these lesions, but there is significant overlap in the immunophenotype of these lesions such that in the individual case, they are not particularly useful. Moreover, diagnoses based on immunohistochemical analysis have yet to be validated by clinical follow-up.23

In a recent study by Odze et al,24 there were no significant differences in the frequencies of LOH (loss of heterozygosity) of 3p, APC or p16 in the UC-associated adenoma-like lesions that occurred within areas of colitis compared to those that occurred in areas not involved by colitis. These data suggest that UC-associated flat dysplastic (non-adenoma-like) DALMs have a different molecular genotype than UC-associated adenoma-like lesions as well as non-UC sporadic adenomas. Furthermore, the latter two lesions may be pathogenetically similar, if not identical, to one another.25

At least at our institution, there has been a trend to assume that any adenoma-like polypoid lesion arising in an area involved by IBD is, in fact, an IBD-associated dysplastic lesion as opposed to a sporadic adenoma (since there is no reliable way to separate between these lesions). As such, our clinicians have been fairly aggressive at resecting such lesions. More recent data suggest that a large proportion of these patients can be safely treated by endoscopic polypectomy, provided that strict criteria are followed. Recently, two articles were published back-to-back in Gastroenterology supporting the role of endoscopic polypectomy for adenoma-like dysplastic lesions in UC.26,27 Authors from the Brigham and Women's Hospital evaluated 24 patients with UC who had an adenoma-like polypoid dysplastic lesion arising in an area involved by ulcerative colitis.26 In all of these patients, there was histologic documentation of UC in the surrounding non-polypoid mucosa. In addition, all lesions were either sessile or pedunculated polyps that were endoscopically and histologically indistinguishable from sporadic adenomas. All patients had numerous other biopsy specimens taken, and there was no evidence of flat dysplasia or carcinoma in any other area of the colon at the time of discovery of the adenoma-like polypoid lesion. All patients were treated by complete polypectomy and had follow-up surveillance colonoscopy with biopsy (mean follow-up period: 42.4 months). Ten patients did not develop any further dysplastic lesions, whereas 14 patients (58%) subsequently had a dysplastic lesion that developed. In two patients, the lesions arose outside of areas involved by the colitis, and thus it can be assumed that these represent sporadic adenomas. Of the 12 patients who subsequently developed an adenoma-like polypoid lesion in an area involved by IBD, one patient had low-grade dysplasia detected in flat mucosa in a colectomy specimen that was performed six months later, but no patient developed adenocarcinoma within the follow-up period. Similar results were obtained from the Mt. Sinai Medical Center.27 Thus, both studies advocate endoscopic polypectomy for adenoma-like dysplastic lesions arising in areas involved by IBD, provided strict criteria are met (Figure 1).

The Problem with Dysplasia
The first problem encountered by the pathologist, gastroenterologist, and ultimately the patient, is the histologic recognition of dysplasia, and its separation from a reparative process. As noted in several studies, there is some degree of intra- and interobserver variability in recognizing dysplasia, particularly in the separation of negative versus indefinite for dysplasia versus low-grade dysplasia.28,29

The utility of dysplasia as a marker of cancer is limited by sampling. Given the huge surface area of the colon, the fact that many foci of dysplasia are not grossly recognizable by the endoscopist, and the current atmosphere of cost containment, the problem of sampling error is obvious. Mapping studies by Levine et al 30 and Rutegard et al 31 have shown that dysplasia may be localized to a small area within the colon, and may require extensive sampling beyond what is clinically or economically feasible. Furthermore, there are limited data that address the frequency and interval of progression from low-grade to high-grade dysplasia to invasive carcinoma. All of these problems (and more) have led to a search for other markers of carcinoma risk in UC. Ideally, such a marker would be more objective than the recognition of dysplasia and provide a high predictive value for the development of carcinoma, while still being associated with a low rate of synchronous carcinoma.32 Such a "magic bullet" marker has not yet been found, and thus the morphologic recognition of dysplasia still remains the best marker of increased cancer risk.

Controversies in Management
There are really three choices for managing patients with long-standing, extensive UC, all of which are associated with pros and cons. One could choose to ignore the risk of dysplasia/cancer entirely or follow the patient clinically, reserving colonoscopy for when new symptoms arise. It does not make sense to perform surveillance colonoscopy if the patient is unwilling or unable to undergo definitive therapy once the surveillance goal (dysplasia) has been achieved. Since most patients with UC do not develop dysplasia or carcinoma, this alternative is reasonable for patients who are not surgical candidates or who are elderly, since it is unlikely that dysplasia or carcinoma would arise within the remainder of the patient's life, particularly if screening colonoscopy is negative for dysplasia.33

Prophylactic colectomy has also been advocated as a possible mode of management in these patients. Certainly, this alternative has the advantage of eliminating the risk of the development of carcinoma, avoids the morbidity and mortality associated with possible development of fulminant colitis and eliminates the need for surveillance colonoscopy. The advent of the ileal pouch-anal anastomosis procedure has made prophylactic colectomy a more attractive option to some patients, particularly young patients who have years of UC-related symptoms and surveillance colonoscopy to endure. Furthermore, prospective studies have shown that patients regard their quality of life as improved following definitive surgical treatment.34 On the other hand, one could argue that this is a radical procedure for an individual patient who, statistically speaking, is unlikely to ever develop dysplasia or carcinoma. In addition, there is morbidity associated with major abdominal surgery as well as complications (pouchitis, anastomotic leak, fistula) which may occur in the surgically constructed pouch. Since there have been no controlled trials that compare survival in patients with UC treated with either prophylactic colectomy or colonoscopic surveillance, there is no direct evidence to support the effectiveness of one over the other. Provenzale et al utilized decision analysis that involves a systematic evaluation of the risks and benefits of a potential strategy to determine if there is any survival advantage with either form of management.35 These authors found that prophylactic colectomy would increase life expectancy by 2-10 months compared with surveillance and by 1.1-1.4 years compared with no surveillance. Surveillance colonoscopy would increase life expectancy by 7 months-1.2 years when compared with no surveillance. This form of analysis requires a certain number of assumptions that may or may not be valid, and the clinical utility of such an analysis is yet to be determined.

Finally, there are pros and cons associated with colonoscopic surveillance in the management of these patients. There are limited prospective data available that assess the efficacy of surveillance in reducing cancer risk and decreasing mortality from IBD-associated carcinoma. Axon recently analyzed the data from 12 studies of colonoscopic surveillance in UC and provided a strong argument against the efficacy of colonoscopic surveillance.36 From these 12 studies, 1916 patients were evaluated with 3807 colonoscopies, and only 92 cancers were detected, only 52 (57%) of which were Dukes' A or B (potential surgical cures). Only 11 (12%) Dukes' A or B cancers were detected on surveillance colonoscopies. Since these results are derived from centers with a strong interest and expertise in the management of UC, one would expect results to be even more disappointing from non-academic centers. More recently, Karlen et al 37 reported that colonoscopic surveillance may be associated with a decreased risk of death from colorectal carcinoma in patients with long standing UC.

Although further studies are required to fully elucidate the cost/benefit ratio of colonoscopic surveillance, at the current time most gastroenterologists recommend this strategy to high-risk UC patients. At the Cleveland Clinic Foundation, we adhere to the following protocol with respect to patient management: Patients with extensive colitis who have had disease for more than 7-10 years are followed with regular colonoscopy with biopsy. If the screening (initial) biopsies are all negative for dysplasia, surveillance intervals of 2-3 years seem reasonable, since the risk of progression is very low.38 Nugent et al found that of 175 patients without dysplasia on initial biopsy, only 6 patients subsequently developed dysplasia, and no patients developed carcinoma within the follow-up interval.33 Patients whose biopsies are interpreted as indefinite for dysplasia require shorter-term follow-up (6 months-1 year), as some of these patients will develop dysplasia and/or carcinoma on subsequent biopsies.33,38 Ideally, biopsies should be taken when the disease is in remission, or at least should be taken from the least inflamed areas, as they are easier to interpret. Recommendations for patients whose biopsies show low-grade dysplasia are controversial. At our institution, these patients are followed more closely, and colectomy is considered if it is associated with a grossly suspicious lesion (dysplasia-associated lesion or mass; DALM), since there is a strong correlation between DALM and synchronous carcinoma.13,39 However, the definition of DALM is broad and includes any raised lesion. If one excludes sessile or pedunculated polyps (as described above) and restricts the definition of a DALM to a broad plaque-like lesion or mass, then we believe that a biopsy diagnosis of low-grade dysplasia in a DALM warrants colectomy. Other possible indications for colectomy include the detection of low-grade dysplasia at more than one site in the colon, or on subsequent endoscopies, or if low-grade dysplasia is detected on initial (screening) colonoscopy. Finally, if high-grade dysplasia is detected, colectomy is recommended.

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FIGURE 1

RECOMMENDED THERAPY FOR ADENOMA-LIKE DYSPLASTIC LESIONS
IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE*

* Modified from reference 26