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Controversies in the diagnosis of Barrett esophagus and Barrett-related dysplasia: one pathologist's perspective.

One of the more common specimens encountered by both general surgical pathologists and gastrointestinal pathologists are esophageal biopsy specimens to "rule out Barrett esophagus (BE)," as well as to assess for the presence or absence of dysplasia in patients with known BE. Barrett esophagus is associated with an increased risk of esophageal adenocarcinoma (1); thus, patients with this condition undergo periodic endoscopic surveillance with biopsies for early detection of dysplasia and malignancy.

This discussion is centered on some of the newer controversies related to BE and BE-related dysplasia. First and perhaps most important, the evolving definition of BE is discussed. Given that this diagnosis implies an increased risk of esophageal adenocarcinoma and perhaps lifelong endoscopic surveillance, it is critically important to gain an understanding as to what constitutes BE. Second, this discussion focuses on the difficulties in recognizing BE-related dysplasia and, in particular, touches on the controversial topic of so-called basal crypt dysplasia (BCD). Finally, although there is often great attention paid to the difficulties of recognizing and agreeing on dysplasia at the low end of the spectrum (negative for dysplasia versus indefinite for dysplasia versus low-grade dysplasia), very little attention has been paid to the upper end of the dysplastic spectrum, that is, the separation of high-grade dysplasia (HGD) from intramucosal adenocarcinoma (IMC) in biopsy specimens.

THE EVOLVING DEFINITION OF BE

The definition of BE has evolved during the years, and it is not necessary to delve too deeply into some of the past definitions of this condition. In 2008, the Practice Parameters Committee of the American College of Gastroenterology published its recently updated guidelines for the diagnosis, surveillance, and treatment of BE. (2) The guidelines state the definition of BE to be a "change in the distal esophageal epithelium of any length that can be recognized as columnar type mucosa at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus." (2) Thus, there are 2 basic components to this definition--an endoscopic abnormality and a histologic alteration characterized by the identification of goblet cells (Figure 1). Although the job of the pathologist is straightforward given this definition, it is amazing how much difficulty and confusion interpretation of these esophageal biopsy specimens can cause. Barrett esophagus can be further subdivided into long-segment ([greater than or equal to] 3 cm) or short-segment (<3 cm) BE, based on the length of involvement of the distal esophagus. (3,4) In addition, some patients show extremely short segments (<1 cm) of BE with very subtle irregularities of the squamocolumnar junction (so-called ultrashort-segment BE). The latter condition may be extremely difficult to distinguish from intestinal metaplasia of the gastric cardia.

As stated in the excellent recent review by Riddell and Odze, (5) based upon prior studies (6-10), "the basis for this definition relies mainly on the fact that most adenocarcinomas of the esophagus develop in Barrett's esophagus mucosa with intestinal metaplasia, in retrospective cohort studies." This, therefore, implies that metaplastic, non-goblet cell-containing columnar epithelium in the distal esophagus does not impart a similar risk of adenocarcinoma and, as such, a diagnosis of BE should not be rendered in the absence of intestinal metaplasia (IM) (Figure 2). However, there is not universal agreement that IM should be required for a diagnosis of BE. For example, the British Society of Gastroenterology does not require IM to establish this diagnosis. (11,12) Similarly, Ogiya et al (13) do not require goblet cells to diagnose this condition but rather simply require the identification of columnar-lined esophagus (CLE).

There are several lines of thought that reasonably challenge the contention that IM should be required for a diagnosis of BE. First, there is some belief that most (if not all) patients with a CLE ultimately develop IM if followed for a long enough period. (14) In truth, there are few data to strongly support this contention. However, there are data to suggest that most patients with at least 2 cm of CLE actually prove to have IM if enough biopsy samples are taken from the CLE segment. (15) In the study by Harrison and colleagues, (15) close to 75% of patients with CLE proved to have IM, but even with extensive biopsy sampling (up to 16 biopsies), about 25% of patients were not found to have evidence of IM. Kim et al (16) found that up to 20% of patients with more than 3 cm of CLE had no evidence of IM. These studies clearly show that sampling error could be a confounding factor, in that some patients with significant lengths of CLE do not have documentation of IM. In reviewing the literature on this topic, I have reached several conclusions. First, the longer the segment of CLE, the more likely IM will be found. Second, the more biopsy samples taken from the CLE, the more likely goblet cells will be sampled. Finally, because goblet cells tend to be found preferentially in the most proximal part of the BE segment, (17) focused samples from this location will give a higher yield of IM.

For years it has been assumed that only intestinalized mucosa predisposes to esophageal adenocarcinoma and hence the reason why the definition of BE (according to the American College of Gastroenterology) relies on the identification of goblet cells. Thus, by inference, this definition suggests that metaplastic, non-goblet cell columnar epithelium in the esophagus is not premalignant. There are recent data to suggest this may not be the case. First, immunohistochemical studies have found that non-goblet cell columnar epithelium is essentially intesfinalized, even though goblet cells are not identified. (18-24) For example, metaplastic non-goblet cell columnar epithelium reveals positivity for markers such as CDX-2, DAS-1, villin, and HepPar1, all of which are also expressed in intestinalized epithelium throughout the gastrointestinal tract, including esophageal IM. Second, several studies have detected molecular alterations in metaplastic non-goblet cell columnar epithelium that are similar to those found in intestinalized mucosa. (25-27) Lui and colleagues, (26) using image cytometry and high-fidelity DNA histograms, found similar DNA content abnormality in these 2 types of epithelia, including peak DNA index, aneuploidy rate, and percentage of cells with DNA greater than 5 N. Both goblet cell and metaplastic non-goblet cell columnar epithelium in patients with BE showed alterations significantly different from those found in gastric controls.

The last line of evidence that calls into question the entirely "benign" nature of metaplastic non-goblet cell columnar epithelium relates to the potential risk of dysplasia and carcinoma. Several studies have found a similar risk of progression in patients with and without goblet cells in CLE. (14,28) For example, Kelty et al (28) found a similar rate of development of esophageal adenocarcinoma in patients with CLE without goblet cells (3.6%) compared with those with goblet cells (4.5%). Similarly, Gatenby et al (14) found a similar rate of progression to low-grade dysplasia, HGD, or carcinoma in patients with CLE with (19.8%) and without (13.2%) goblet cells in their index endoscopy. Finally, in studies of esophagectomy specimens with esophageal adenocarcinoma, especially those with a very short segment of CLE, some of these tumors appear to arise in CLE without goblet cells, even with very detailed morphologic study with extensive sectioning. (29-31) In essence, these studies challenge the long-held belief that all BE-associated adenocarcinomas arise in the setting of intestinalized mucosa.

In summary, as of the current time, the American College of Gastroenterology requires the recognition of goblet cells to render a definitive diagnosis of BE. This, however, is not true in other parts of the world. Although many US pathologists have embraced the absolute necessity of identifying goblet cells in biopsy specimens to make this diagnosis, an open mind is required because some emerging data have shown CLE with and without goblet cells have immunohistochemical and molecular similarities. A change in the definition of BE to include those patients with CLE without goblet cells would obviously have enormous clinical and economic implications.

BE-RELATED DYSPLASIA

In our consultation practice, by far the most common question is the presence (and degree) or absence of dysplasia arising in a background of BE. Dysplasia can be defined as the presence of neoplastic epithelium that is confined within the basement membrane of the gland within which it arises. (32) Unlike inflammatory bowel disease (IBD)-associated dysplastic lesions, at least in my opinion, most cases of BE-related dysplasia do not closely resemble colonic adenomas. Rather, the typical form of BE-related dysplasia often arises in glands that retain their normal configuration and often lack nuclear stratification. Using the criteria as defined by Riddell et al (32) for dysplasia arising in IBD, dysplasia in BE can be classified as either low grade or high grade based on the degree of the abnormality present. Thus, the possibilities include (1) negative for dysplasia; (2) positive for dysplasia, either low-grade dysplasia or HGD; or (3) indefinite for dysplasia. As pointed out by Dr Appelman, (33) the criteria for defining dysplasia in BE were derived from those defined originally in IBD. In fact, if one attempts to trace back the original criteria for BE-related dysplasia, it is a fruitless endeavor and inevitably leads back to those defined for IBD in the seminal 1983 article published in Human Pathology. (32) Nevertheless, an attempt will be made here to put into words what is extremely difficult to define.

In low-grade dysplasia, crypt architecture tends to be preserved with only minimal distortion, and cytologically atypical nuclei are limited to the basal half of the crypts (Figure 3). The nuclei tend to show variable hyperchromasia, overlapping cell borders with nuclear crowding, and irregular nuclear contours. Dystrophic goblet cells may be seen, although typically goblet cell numbers are markedly reduced. Separation of low-grade dysplasia from regenerative changes is discussed later.

Simply put, HGD shows more severe cytologic and architectural changes than are present in low-grade dysplasia (Figure 4). Architecturally, there tends to be more crypt distortion in HGD, sometimes with a villiform configuration of the mucosal surface and/or branched or cribriform crypts. Cytologically, the cells show more nuclear pleomorphism and hyperchromatism than is seen in low-grade dysplasia, and there often is nuclear stratification to the crypt luminal surface.

A diagnosis of "indefinite for dysplasia," much to our clinical colleagues' dismay, is a legitimate diagnosis. The differentiation of regenerative changes from true dysplasia, particularly in a background of inflammation or ulceration, is at times difficult if not impossible. Thus, if the pathologist is unsure as to whether the epithelial changes are regenerative or truly dysplastic, a diagnosis of indefinite for dysplasia should be rendered. In some cases, one may not be sure if one is dealing with regenerative or dysplastic changes, even in the absence of inflammation, and a diagnosis of indefinite for dysplasia is acceptable under these circumstances as well.

DISTINGUISHING BETWEEN REGENERATIVE CHANGES AND DYSPLASIA

Because BE mucosa is metaplastic, there is a "baseline atypia" that is always present and in a sense must be overlooked to make a diagnosis of dysplasia. This baseline atypia is most pronounced in the glands at the base of the mucosa and does not involve the surface epithelium. In addition, biopsies from Barrett mucosa are often inflamed, often with both acute and chronic inflammatory cells. As in the case of active chronic IBD, neutrophil-mediated epithelial injury can induce regenerative cytologic changes that may be difficult to differentiate from dysplasia. Several rules that I follow in making a diagnosis of dysplasia include:

1. I am conservative about making a diagnosis of dysplasia in the face of neutrophil-mediated epithelial injury. Although neutrophils can be found within dysplastic epithelium, the changes have to be convincing in order for me to make a definitive diagnosis of dysplasia. Otherwise, I usually make a diagnosis of indefinite for dysplasia if I am unsure or negative for dysplasia if the changes are clearly regenerative.

2. The low-magnification appearance of the mucosa is extremely important because the cytologic changes are typically recognizable at low magnification. A focus usually "catches my eye" and causes me to go to a higher magnification to confirm a diagnosis of dysplasia.

3. I like to see cytologic changes on the surface epithelium not just in the glandular compartment. In a well-oriented specimen, it is straightforward to determine whether the cytologic changes involve the surface epithelium. On the other hand, in a tangentially sectioned biopsy specimen, this evaluation can be extremely difficult.

The reader should be aware of the emerging concept of BCD, as recently described by Lomo and colleagues. (34) There is evidence to suggest that BE-related dysplasia begins in the crypt bases and progresses to involve the full length of the crypts and surface epithelium. Thus, BCD has been proposed to be a form of dysplasia that can be recognized prior to surface involvement (ie, in the face of surface maturation). Morphologically, BCD has all of the features of traditional low-grade dysplasia but is limited to the crypt bases and is devoid of active inflammation. In the study by Lomo et al, (34) 47% of cases of BCD (in 15 patients) were associated with full-thickness dysplasia elsewhere. Molecular studies have also found similar alterations in BCD when compared with traditional dysplasia; these alterations are different from those found in nondysplastic epithelium. (35)

A myriad of features are useful in separating repair from dysplasia, although I believe some features are more important than others. Dysplastic epithelium tends to show variable nuclear hyperchromasia and pleomorphism. Some cells look different from their neighbors, with some showing nuclear hyperchromasia and pleomorphism when compared with surrounding cells within the same crypt. In contrast, although both nuclear hyperchromasia and pleomorphism may be seen in repair, the changes tend to be less severe and more uniform, with cells resembling their neighbors within the same crypt or in adjacent crypts. Thus, the cytologic atypia associated with repair is more uniform than is seen in dysplasia. Dysplastic cells also tend to have a higher nuclear to cytoplasmic ratio as well as irregular nuclear contours. Although regenerative cells may have nuclear size similar to those seen in dysplasia, there tends to be a commensurate increase in the amount of cytoplasm such that the nuclear to cytoplasmic ratio is normal or only mildly increased. In addition, regenerative cells tend to have round and regular nuclear contours.

SAMPLING ERROR AND OBSERVER VARIATION IN THE DIAGNOSIS OF BARRETT-RELATED DYSPLASIA

In any given case, dysplasia may be diffusely distributed throughout a segment of BE or may be extremely focal. Even using a rigorous sampling technique (4-quadrant biopsies for every 1 to 2 cm of BE using jumbo biopsy forceps), small foci of dysplasia can be left unsampled. The need for thorough sampling is further emphasized by the fact that many examples of HGD or early adenocarcinoma arising in BE are not associated with a grossly recognizable lesion.

Another problem facing both the pathologist and the gastroenterologist (and for that matter the thoracic surgeon) is both the intraobserver and interobserver variation in the diagnosis of dysplasia. Given the subtle gradation of changes from baseline atypia to low-grade dysplasia to HGD, it is not surprising that this variation exists. Reid et al (36) found that this variation was most striking at the low end of the scale: distinguishing negative for dysplasia from low-grade dysplasia or indefinite for dysplasia. A more recent study using k statistics by Montgomery and colleagues (37) confirmed a high degree of intraobserver and interobserver variation in the separation of these diagnoses, even among pathologists with a special interest in gastrointestinal pathology.

CAN WE SEPARATE BAD FROM WORSE? THE PROBLEM OF HGD VERSUS IMC

As treatment options broaden for patients with BE with HGD and "early adenocarcinoma," some advocates of nonsurgical treatments (including intensive endoscopic surveillance, ablative therapy such as a photodynamic therapy, or endoscopic mucosal resection) have proposed that "surgical resection of the esophagus should be reserved for those patients in whom cancer has been documented by biopsy." (38) These recommendations, therefore, rest on the assumption that pathologists can reliably discriminate between HGD and IMC in biopsy specimens. Given the fact that lymphatic channels are present within the esophageal mucosa, there is a small but definite risk of lymph node metastasis, even in patients with IMC. (39)

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Recently, several studies have focused on observer variability in separating HGD from IMC in biopsy specimens. Downs-Kelly et al (40) evaluated preselected slides from 168 patients who were treated by esophagectomy for a diagnosis of HGD, IMC, or submucosal invasive adenocarcinoma (SMC). A preresection biopsy specimen from each case showing the most severe histologic abnormality regarding HGD, IMC, or SMC was selected for review by 7 gastrointestinal pathologists, using well-defined consensus histologic criteria. Each case was then placed in 1 of 4 diagnostic categories by each pathologist: 1, HGD; 2, HGD with marked distortion of glandular architecture, cannot exclude IMC (so-called HGD/MAD); 3, IMC; and 4, SMC.

High-grade dysplasia was defined according to the published criteria by Reid et al, (36) Montgomery et al, (37) and Odze, (41) incorporating both cytologic and architectural changes. Cytologic changes include stratified, hyperchromatic nuclei with nuclear enlargement and an increased nuclear to cytoplasmic ratio, presence of prominent nucleoli, increased mitotic figures, and loss of nuclear polarity. These cytologic changes involve both the crypt and surface mucosa. Architectural changes include increased crypt complexity with crowding, branching, and cribriform formation along with variability of crypt size and shape.

Intramucosal carcinoma is defined as a neoplasm that has invaded into the surrounding lamina propria or muscularis mucosae but not into the submucosa (Figure 5). However, well-defined histologic criteria for establishing this diagnosis have not been published. Four criteria were arbitrarily defined to establish a diagnosis of IMC in this study, including single-cell invasion of the lamina propria in more than 1 focus, sheets of cells obliterating the lamina propria, small angulated so-called abortive glands invading the lamina propria, or a never-ending anastomosing gland pattern similar to endometrial adenocarcinomas of the uterine corpus. Only 1 feature met the criteria for SMC--unequivocal stromal desmoplasia.

Three criteria were arbitrarily used to establish a diagnosis of HGD/MAD, including glandular crowding with loss of intervening lamina propria, cribriform growth, or prominent (at least 3) dilated glands with intraluminal necrotic debris (Figure 6).

The results of this study are intriguing. There was 100% agreement among all 7 pathologists in only 12 of 163 (7.4%) cases. Overall, most (at least 4 of 7) pathologists agreed in 85.9% of cases. However, following k statistical analysis, the overall agreement for all 4 diagnostic categories was only fair ([kappa] = 0.30). Cases interpreted as HGD had the best agreement ([kappa] = 0.47, moderate agreement), whereas those with SMC had the lowest [kappa] score ([kappa] = 0.14, poor agreement). HGD/MAD and IMC had [kappa] scores between these 2 extremes ([kappa] = 0.21 and 0.30, respectively, or fair agreement). Based on these results, the authors called into question management decisions based upon the distinction of these diagnostic categories in pretreatment biopsy specimens.

In a more recent study, Zhu and colleagues (42) from the University of Michigan (Ann Arbor) attempted to ascertain the prevalence of carcinoma in esophagi resected for HGD or HGD "suspicious for carcinoma" (HGD/S) diagnoses in pretreatment biopsy specimens. Based on the original diagnoses, carcinoma was found in 15 of 89 (17%) HGD cases and 28 of 38 (74%) HGD/S cases. However, these authors attempted to more precisely define the HGD and HGD/S categories. The latter category included those cases with solid or cribriform arrangements, ulcers occurring within the high-grade dysplastic mucosa, dilated dysplastic tubules containing necrotic debris, large numbers of neutrophils within the high-grade dysplastic epithelium, and dysplastic tubules that were incorporated into overlying squamous epithelium. Following reclassification of the biopsy specimens into these categories, only 1 of 21 (5%) cases with HGD were found to harbor a carcinoma in the esophagectomy specimen. Of 25 cases reclassified as HGD/S, 18 of 25 (72%) had carcinoma, as did 17 of 23 (74%) reclassified as adenocarcinoma (used only for clearly invasive lesions, either clear-cut IMC or SMC). These authors concluded that it is actually quite rare to find an invasive lesion in an esophagectomy performed for HGD using rigorous criteria. HGD/S is a biopsy diagnosis that is more closely associated with an invasive lesion in the esophagectomy specimen; the more individual "suspicious" features found in the biopsy specimen, the more likely an invasive lesion would be found.

Recently, Patil and colleagues (43) from Cleveland Clinic (Cleveland, Ohio) attempted to compare the Cleveland Clinic (as defined by the Downs-Kelly study) and the University of Michigan (as defined by the Zhu study) systems, as well as correlating preresection biopsy diagnosis with the final resection diagnosis with the hope of identifying histologic features in biopsy specimens that might be predictive of invasive adenocarcinoma on esophagectomy. Using the Cleveland Clinic system, only those cases in which there was a consensus agreement (at least 4 of 7 pathologists agreed) were used for the purposes of this study. Thus, of the 168 preresection biopsy specimens, 112 biopsy samples had a consensus diagnosis, including 32 with HGD (29%), 32 with HGD/ MAD (29%), 45 with IMC (40%), and 3 with SMC (2%). Of these 112 biopsy samples, 83 (74%) had adenocarcinoma found in the esophagectomy specimen, including 59 with IMC and 24 with SMC. Applying the University of Michigan system to the biopsy series, excellent diagnostic agreement was found between the Cleveland Clinic and University of Michigan systems ([kappa] = 0.86). Both systems showed significant correlation between preoperative biopsy diagnosis and esophagectomy diagnosis (P < .001). The likelihood of finding adenocarcinoma in the resection specimen was significantly higher with HGD/ MAD (using the Cleveland Clinic criteria) or HGD/S (using the University of Michigan criteria), compared with HGD alone. The presence of an endoscopic lesion, a never-ending glandular pattern, sheetlike growth, angulated glands, 3 or more dilated glands with intraluminal debris, and 1 or more foci of single-cell infiltration into the lamina propria increased the odds of finding adenocarcinoma in the resection specimen. The latter 2 variables remained independent predictors of invasive adenocarcinoma in multivariable analysis. Thus, this study shows that there are specific histologic features that can be identified in preresection biopsy specimens that are highly predictive of finding an invasive adenocarcinoma in the esophagectomy specimen.

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(43.) Patil DT, Goldblum JR, Plesec T, et al. Prediction of adenocarcinoma on esophagectomy from pre-resection biopsies of Barrett's esophagus with at least high-grade dysplasia: a comparison of two systems. Mod Pathol. 2010;23(suppl 1):161A.

John R. Goldblum, MD

Accepted for publication June 3, 2010.

From the Department of Anatomic Pathology, ClevelandClinic Lerner College of Medicine, Cleveland Ohio.

The author has no relevant financial interest in the products or companies described in this article.

Presented at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting, University of Michigan, Ann Arbor, October 10, 2009.

Reprints: John R. Goldblum, MD, Department of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Ave L25, Cleveland, OH 44195 (e-mail: goldblj@ccf.org).
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