—  SHORT COURSE  —

A PRACTICAL APPROACH TO GASTROINTESTINAL PATHOLOGY


INTESTINAL METAPLASIA OF THE ESOPHAGOGASTRIC JUNCTION, DYSPLASIA AND CARCINOMA

John R. Goldblum, M.D.




Barrett's esophagus (BE) is a complication of chronic gastroesophageal reflux and results in the replacement of the normal stratified squamous epithelium of the esophagus with columnar epithelium of various types.1 Risk factors for the development of BE in patients with gastroesophageal reflux disease (GERD) include the presence of a hiatal hernia, duodeno-gastric reflux, delayed esophageal acid clearance times and decreased resting pressure of the lower esophageal sphincter (LES).2-4 The importance of diagnosing BE is related to its association with the subsequent development of esophageal adenocarcinoma,5  the frequency of which has rapidly increased over the past several decades.6,7

The Normal Esophagus
In order to properly make a diagnosis of BE, it is important to understand the normal anatomy and histology of the esophagogastric junction (EGJ), including the lower esophageal sphincter (LES). The muscular EGJ is the site at which the most distal portion of the esophagus (the distal most segment of the LES) meets the proximal stomach. Endoscopically, one can closely approximate the muscular EGJ by identifying the proximal margin of the gastric folds.8   The mucosal EGJ, also known as the mucosal squamocolumnar junction (SCJ) or Z-line, is the site at which the squamous mucosa of the esophagus meets columnar-lined mucosa. It is important to understand, however, that the SCJ may be at the same level as the muscular EGJ, or may lie 1-2 cm above the muscular EGJ in "normal" individuals. Thus, cardiac and fundic-type mucosae may be found within the distal few centimeters of the esophagus in "normal" individuals, presumably related to physiologic reflux. Several studies from the group at the University of Southern California (USC) have shown that metaplastic cardiac-type mucosa in the distal esophagus is quite common and is strongly associated with acid reflux.9-11

The Normal Gastric Cardia: Fact or Fiction?
The very existence of the gastric cardia as a normal structure has been the source of great controversy. Most textbooks describe the gastric cardia as a narrow strip of mucosa that separates the most distal portion of the esophageal squamous mucosa from the acid-producing fundic mucosa.12   However, recent data from the USC group suggest that the gastric cardia is not a normal structure, but rather that cardiac-type mucosa is metaplastic.9-11,13   Recently, Kilgore et al evaluated the entire EGJ in 30 pediatric autopsies from patients 18 years of age or younger with no known history of GERD or BE.14   In each case, the squamocolumnar junction and its relationship to the EGJ was meticulously noted. In all cases, cardiac mucosa was present, always on the gastric side of the EGJ, although it was quite small, ranging from only 1 to 4 mm in length. The results of this study support the concept that the gastric cardia is present from birth as a normal structure, although it does not preclude the possibility that cardiac-type mucosa can arise in the distal esophagus as a metaplastic phenomenon, as proposed by the group from USC.

The Endoscopic Diagnosis of Barrett's Esophagus
Endoscopically, it may be difficult for the gastroenterologist to definitively identify the presence of BE for several reasons.15   First, the presence of a hiatal hernia, a frequent accompaniment of BE, makes identification of the muscular EGJ difficult. Furthermore, there are no anatomic landmarks that clearly define the region of the LES. Thus, it may not be known either to the endoscopist or the pathologist precisely where a biopsy specimen may have come from in relation to the EGJ. A biopsy from the vicinity of the EGJ with intestinal metaplasia could either represent BE or intestinal metaplasia of the most proximal portion of the stomach. The significance of distinguishing between these two conditions will be discussed at length below.

The Histologic Diagnosis of Barrett's Esophagus


Case 6 - Intestinal Metaplasia of the Gastric Cardia, Probably Secondary to H. Pylori-related Multifocal Atrophic Gastritis
Case 6 - Intestinal Metaplasia of the Gastric Cardia, Probably Secondary to H. Pylori-related Multifocal Atrophic Gastritis. Stain is alcian blue at pH 2.5.

In 1976, Paull et al described three different types of epithelium in BE: fundic-type, cardiac-type (junctional) and specialized columnar epithelium.16   The cardiac and fundic-types of Barrett's epithelium resemble their normal counterparts in the stomach, except for the presence of some degree of mucosal distortion, glandular atrophy and mild inflammation.16,17   A biopsy from the "distal esophagus" with either of these mucosae is not diagnostic of BE since, as stated earlier, these mucosae are frequently found in the distal esophagus in the absence of intestinal metaplasia.9-11   If the endoscopic impression is clearly that of BE, then the absence of intestinal metaplasia may simply be a function of sampling error. Thus, although the pathologist may not be able to make a definitive diagnosis of BE in this situation, the endoscopic impression may still strongly suggest this diagnosis. Fortunately, this problem is relatively rare, as Weinstein et al found non-intestinal tongues of columnar epithelium extending more than 2 cm into the lower esophagus in less than 1% of 250 cases of BE which were studied.18  If one performs an alcian blue stain (pH 2.5), one may find isolated goblet cells which were not readily identifiable on hematoxylin and eosin-stained sections in areas that otherwise resemble cardiac or fundic-type mucosae. When these mucosae are found in a patient who is known to have BE, they are typically present in the most distal portion of the Barrett's segment, often with a zonation from specialized columnar epithelium found most proximally, fundic-type mucosa found most distally, with cardiac-type mucosa in between, although a mosaic pattern may also be identified.16  


Case 7 - Specialized Columnar Epithelium Consistent with Barrett's Esophagus and High Grade Epithelial Dysplasia
Case 7 - Specialized Columnar Epithelium Consistent with Barrett's Esophagus and High Grade Epithelial Dysplasia
Case 7 - Specialized Columnar Epithelium Consistent with Barrett's Esophagus and High Grade Epithelial Dysplasia

The presence of specialized columnar epithelium, characterized by acid-mucin-containing goblet cells, has been accepted as diagnostic of BE, regardless of the precise site of the biopsy within the tubular esophagus.17,18   In fact, the American College of Gastroenterology and its Practice Parameters Committee recently provided a definition of BE as "a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy."19   BE can be further (arbitrarily) divided into short (SSBE) and long (LSBE) segment BE on the basis of the length of esophageal intestinal metaplasia: less than 3 cm and greater than or equal to 3 cm, respectively.20,21   Histologically, specialized columnar epithelium is characterized by two cell types - goblet cells and columnar cells. Cytologically, goblet cells have distended, mucin-filled cytoplasm with a barrel-shaped configuration. Histochemically, goblet cells contain acid mucins (both sialo and sulfated mucins) which stain positively with alcian blue at pH 2.5. The columnar cells in between the goblet cells may resemble either gastric foveolar cells or intestinal absorptive cells, at least at the light microscopic level. Unlike normal gastric foveolar cells which contain neutral mucin, the columnar cells in BE may contain alcian blue-positive acid mucin ("the columnar blues"), although the intensity of staining is not as intense as in the goblet cells.22  Such cells should not be used as definitive evidence of BE since unequivocal goblet cells are required for this diagnosis.

Is All Intestinal Metaplasia Equivalent To Barrett's Esophagus?
Spechler and colleagues were the first to report that adults frequently have unrecognized segments of intestinal metaplasia in the region of the EGJ.23   Among 142 patients without endoscopically apparent BE (defined as greater than 3 cm of specialized columnar epithelium above the EGJ), 26 (18%) were found to have intestinal metaplasia in this location. Subsequent studies reported the prevalence of intestinal metaplasia near the EGJ to range from 9% to as high as 36%,24-26   with an average of approximately 18%. While some have found intestinal metaplasia in this location to be associated with symptoms of GERD,24   others found it to be associated with increased age.25,26   In fact, there are no consistent associations with intestinal metaplasia among these studies, perhaps reflecting the fact that these studies are comparing "apples to oranges" - that is, some of these patients likely have intestinal metaplasia in the distal esophagus whereas others may have intestinal metaplasia in the gastric cardia.

There are problems with equating intestinal metaplasia near the EGJ to BE in all cases. Histologically, intestinal metaplasias of the upper stomach and distal esophagus are indistinguishable by light microscopy and histochemical methods.27   Furthermore, the endoscopist may not be entirely sure of whether the biopsy specimen with intestinal metaplasia came from above or below the EGJ, given the difficulty in locating this landmark. Thus, the issue as to whether intestinal metaplasia in the gastric cardia (CIM) has the same etiology and significance as BE becomes central to determining whether it is important to distinguish between these two conditions.

Intestinal Metaplasia of the Gastric Cardia (CIM)
Over the past several years, it has become apparent that CIM is also a relatively common finding, with prevalence rates ranging from 5.3%28   to as high as 23%29   of adults who present for upper endoscopy. Differences in patient population and number of biopsy specimens obtained may account for the variability in the prevalence of CIM reported in these studies. For example, Morales et al performed their study at a VA hospital, where 95% of the participants were men and the mean age was 62 years (prevalence of CIM: 23%).29   In addition, five biopsy specimens from the cardia were obtained in each patient, whereas in the study from the Cleveland Clinic Foundation, only two cardia biopsy specimens were obtained, with a prevalence of CIM of 9%.30   If CIM is patchy in distribution, then it would be logical to assume a higher yield if more biopsy specimens are obtained.

The data on the relative roles of H. pylori infection and GERD in the development of CIM are conflicting. Öberg et al found that intestinal metaplasia in this location was strongly associated with the hallmarks of GERD, including increased esophageal acid exposure, a hiatal hernia, a defective LES, and erosive esophagitis.10   In addition, there was a tendency for the features of GERD to be worse in patients with intestinal metaplasia compared to those without. Only 17% of the patients with CIM had H. pylori infection documented in the cardia, and only 6.9% had intestinal metaplasia in other portions of the stomach. However, Hackelsberger and colleagues found that patients with an endoscopically unremarkable squamocolumnar junction and intestinal metaplasia frequently had H. pylori infection as well as intestinal metaplasia in other parts of the stomach.31   In contrast, in patients with endoscopic features of BE, intestinal metaplasia near the EGJ was associated with male sex and hallmarks of GERD. Similar results were reported in a large study of over 1,000 patients by Hirota et al.28   In our study, CIM was more common among controls (22%) than GERD patients (3%); all patients with CIM had carditis, and the majority had evidence of H. pylori infection as well as intestinal metaplasia in other portions of the stomach.30   The significance of intestinal metaplasia near the EGJ in an individual patient should be evaluated in the context of endoscopic findings, histologic and serologic data for H. pylori infection and information obtained from biopsies of the distal stomach.

Barrett's Esophagus versus CIM: What Is the Risk of Progression to Dysplasia and Adenocarcinoma?
Although all patients with BE are at an increased risk for developing adenocarcinoma, certain patients are at higher risk than others. For example, epidemiologic data suggest that the majority of patients with BE-associated adenocarcinoma are elderly white males.1,32   There is also evidence to support the contention that only those patients with specialized columnar epithelium are at an increased risk of developing Barrett's-related adenocarcinoma.19,33-35   The presence of epithelial dysplasia, particularly high-grade dysplasia (HGD), is also a risk factor for synchronous or metachronous adenocarcinoma.36-38   Several retrospective studies have noted the frequency with which dysplasia is seen both adjacent to and distant from Barrett's-related adenocarcinomas.1   Prospective studies have also documented the progression from specialized columnar epithelium to HGD and eventually invasive adenocarcinoma.35,39   Thus, dysplasia is not only a marker of adenocarcinoma, but it clearly is the pre-invasive lesion. Finally, although it is known that adenocarcinoma can arise in extremely short segments of BE,40   some have proposed that there is an increased risk of adenocarcinoma as the length of the BE increases.28,41  

Although there are sparse prospective data available, several studies have indicated a much lower risk of CIM to progress to dysplasia or carcinoma when compared to either SSBE or LSBE. For example, Sharma et al found only one of 34 patients with CIM to progress to dysplasia (low-grade) within the follow-up period.42   Similarly, Morales et al found dysplasia (low-grade) in only one of 28 patients with follow-up periods ranging from 12-46 months (mean 2.5 years).43   Among 85 patients with CIM, Goldstein reported that only 10 of the 85 patients had CIM on repeat biopsy, and none developed dysplasia.44   These data reiterate the importance of attempting to distinguish CIM from intestinal metaplasia of esophageal origin in biopsy specimens, given the apparent differences in the risk of progression to dysplasia or carcinoma.

Ancillary Techniques in Distinguishing Barrett's Esophagus from CIM - Cytokeratin Subset Immunostaining
Given the difficulty in determining the precise site of a biopsy specimen and the histologic resemblance of intestinal metaplasia in both of these locations, it would be of clinical importance to localize the intestinal metaplasia to either the distal esophagus or proximal stomach. Immunohistochemical stains for cytokeratin (CK) subsets may be useful in this regard. Ormsby et al. evaluated CK 7 and 20 immunoreactivity patterns in resection specimens with LSBE and compared them to distal gastric resection specimens with intestinal metaplasia.45   Virtually all cases with LSBE were characterized by superficial and deep CK7 immunoreactivity, with only superficial CK20 staining. In contrast, distal gastric intestinal metaplasia was characterized by patchy superficial and deep CK20 staining in areas of incomplete intestinal metaplasia, strong superficial and deep CK20 staining in areas of complete intestinal metaplasia and patchy or absent CK7 staining in either type of gastric intestinal metaplasia. As an extension of this work, Ormsby et al evaluated the utility of CK subsets in distinguishing intestinal metaplasia of the distal esophagus from that found in the gastric cardia in endoscopic biopsy specimens.46   Patients with CIM all had a normal-appearing Z-line, and biopsies were obtained with the endoscope in a retroflexed position. The "Barrett's CK7/20 pattern" (described above) was found in all 34 cases of LSBE but was absent in all 13 cases of CIM. Thus, although these data must be validated in other laboratories, CK subset immunoreactivity patterns may be useful in distinguishing these forms of intestinal metaplasia near the EGJ, which may have implications in terms of endoscopic surveillance given the apparent differences in cancer risk.

Using identical immunohistochemical stains, Glickman et al47  found that cases of SSBE and LSBE had similar CK staining patterns and were identical to those described by Ormsby et al. However, these authors did not find intestinal metaplasia of the EGJ to have a distinctive CK profile from that seen in SSBE. Given these discrepant results, cases from these two institutions (Cleveland Clinic Foundation and Brigham and Women's Hospital) were exchanged and immunostained at the other institution with interpretation of the CK immunostains by gastrointestinal pathologists at the other institution.48   The major source of disagreement between these two institutions related to the interpretation of weak and patchy CK 7 staining of deep intestinalized glands in Hollande's-fixed Cleveland Clinic cases. Careful review of these slides allowing for the effects of Hollande's fixation on CK 7 immunoreactivity resolved the disagreements in all discrepant cases, all of which were reclassified as having a Barrett's CK 7/20 pattern. Thus, there is excellent interinstitutional reproducibility and high sensitivity and specificity of a Barrett's CK 7/20 pattern in distinguishing SSBE and LSBE from CIM if one accounts for the effect of Hollande's fixation on CK 7 immunostaining.

Cancer Surveillance in Barrett's Esophagus
Although cancer surveillance is performed in most institutions once a diagnosis of BE is rendered, the true cost/benefit ratio of this endeavor is still essentially unknown. In other words, does the increased risk of adenocarcinoma in these patients justify the cost of a cancer surveillance program, particularly one that has so many inherent problems, as will be discussed below? Although this issue has yet to be resolved, at our institution, patients are placed into a cancer surveillance program once a diagnosis of BE has been clearly established, with the surveillance goal being the identification of epithelial dysplasia in a biopsy specimen, before carcinoma has intervened. We essentially follow the protocol proposed by Reid et al36  with 4-quadrant biopsies taken at intervals of 2 cm or less throughout the length of the Barrett's segment, with additional biopsies of any endoscopic lesions, using jumbo forceps.49  

Histopathologic Diagnosis of Dysplasia
Dysplasia can be defined as the presence of neoplastic epithelium that is confined within the basement membrane of the gland within which it arises.50  Unlike inflammatory bowel disease-associated dysplastic lesions, most cases of Barrett's-related dysplasia do not closely resemble colonic adenomas. Rather, the typical form of Barrett's-related dysplasia often arises in glands which retain their normal configuration, and often lack nuclear stratification. Using the criteria defined by Riddell et al for dysplasia arising in inflammatory bowel disease, dysplasia in BE can be classified as either low-grade or high-grade based upon the degree of the abnormality present. Thus, the possibilities include 1) negative for dysplasia; 2) positive for dysplasia, either low-grade or high-grade; or 3) indefinite for dysplasia.

In low-grade dysplasia (LGD), crypt architecture tends to be preserved with only minimal distortion, and cytologically atypical nuclei are limited to the basal half of the crypts. 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 in dysplastic foci. Separation of LGD from regenerative changes will be discussed below.

Simply put, HGD shows more severe cytologic atypia and architectural complexity than are present in LGD, and in some cases this distinction is quite difficult. Architecturally, there tends to be more crypt complexity 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 LGD, and there often is nuclear stratification to the crypt luminal surface.

Separation of intramucosal adenocarcinoma (IMC) from HGD is important, but in some cases is exceedingly difficult. By definition, in IMC, neoplastic cells have penetrated through the basement membrane and infiltrate into the lamina propria, typically as single cells or in small clusters. Given the presence of lymphatic channels within the esophageal mucosa, there is a small but definite risk of regional lymph node metastasis in patients with IMC.51,52  Therapeutic strategies that are based upon the histologic separation of HGD from IMC should be looked at with skepticism, given the great difficulty in their histologic separation.53 

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 made. In some cases, glandular atypia may be striking in the absence of definitive cytologic atypia on the surface epithelium, and under these circumstances, a diagnosis of indefinite for dysplasia is acceptable as well (described further below).

Distinguishing Between Regenerative Changes and Dysplasia
Because Barrett's mucosa is metaplastic, there is a "baseline atypia" which is always present and in a sense must be overlooked in order 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's mucosa are not infrequently inflamed, often with both acute and chronic inflammatory cells. As in the case of active chronic inflammatory bowel disease, neutrophil-mediated epithelial injury can induce regenerative cytologic changes that may be difficult to differentiate from dysplasia. There are some general rules that are useful in distinguishing between these conditions, as outlined below.

One should be conservative about making a diagnosis of dysplasia in the face of active inflammation. Although neutrophils can be found within dysplastic epithelium, the changes have to be convincing in order to make a definitive diagnosis of dysplasia. Otherwise, a diagnosis of indefinite for dysplasia is appropriate unless the changes are clearly regenerative.

The low-magnification appearance of the mucosa is extremely important. True dysplasia usually draws attention at low magnification due to the consistent presence of nuclear hyperchromasia. Obviously, confirmation of cytologic atypia at a higher magnification is necessary. In addition, the cytologic alterations should be present on the surface epithelium, not just in the glandular compartment. In a well-oriented specimen, it is fairly straight-forward to determine whether these cytologic alterations involve the surface epithelium. However, in a tangentially sectioned biopsy specimen, this evaluation can be difficult.

Cytologically, dysplastic epithelium tends to show variable nuclear hyperchromasia and pleomorphism. In other words, cells tend to look different from their neighbors with some showing nuclear hyperchromasia and irregular nuclear contours when compared to 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 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's-related Dysplasia
In any given case, dysplasia may be diffusely distributed throughout a BE segment, or the changes may be focal, sometimes limited to a small area of one fragment in a patient with multiple specimens. When dysplasia is diffuse, using the 4-quadrant biopsy technique previously described, there will be a high frequency of detecting the dysplastic foci. However, even using this rigorous sampling technique, 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.36,49  Given this sampling error, once a diagnosis of dysplasia is made, subsequent biopsies without dysplasia should not lull the gastroenterologist into a false sense of security, provided that the original diagnosis was correct.

Another problem facing the pathologist and the gastroenterologist (and for that matter the thoracic surgeon and ultimately the patient) is both the intra? and interobserver variation in the diagnosis of dysplasia. Given the subtle gradation of changes from baseline atypia to LGD to HGD, it is not surprising that this variation exists. Reid et al found this variation to be most striking at the low end of the histologic spectrum - that is, distinguishing negative for dysplasia from LGD or indefinite for dysplasia.54  The study by Reid et al describes observer variation in terms of percentage agreement, which does not account for agreement that is likely to occur by chance alone. A more recent study by Montgomery et al using kappa statistical analysis (which does account for agreement that occurs by chance alone) confirmed a high degree of intra- and interobserver variation in the separation of these diagnoses, even among pathologists with a special interest in gastrointestinal pathology.55 

Natural History of High-Grade Dysplasia
As previously mentioned, HGD is frequently seen in the mucosa adjacent to invasive esophageal adenocarcinomas and is felt to represent the immediate precursor lesion. However, HGD also is a marker of synchronous or metachronous adenocarcinoma. Approximately 30 to 40% of esophagi resected for HGD harbor an unsuspected adenocarcinoma.33,34,39,49,56  In fact, in our own experience at the Cleveland Clinic Foundation, even with extensive preoperative sampling, patients with a preoperative diagnosis of HGD in the absence of a grossly identifiable lesion still had a more deeply invasive carcinoma in the esophagectomy specimen in 33% of cases.49  However, Reid et al reported excellent success at detecting early carcinomas arising in Barrett's-related HGD in patients who were followed with four-quadrant 1 cm endoscopic biopsy protocols performed at closely timed intervals.57  In a recent prospective study of patients with unifocal HGD with long-term follow-up by Weston et al,58  8 of 15 patients (53%) progressed to either invasive carcinoma or multifocal HGD. The authors concluded that unifocal HGD has a high risk for progressing to multifocal HGD or invasive carcinoma and discouraged an observational approach when this diagnosis is rendered.

Recently, a large study of patients with BE-related HGD from the Hines VA Hospital suggested that surveillance endoscopy with biopsy is a valid and safe follow-up strategy for patients with HGD without cancer.59  Of 1,099 patients with BE, 79 (7.2%) initially had HGD, including 34 patients with prevalent HGD and 45 patients who subsequently developed HGD (incident HGD) without evidence of cancer. In four of these 79 patients, rigorous endoscopy and biopsy detected an unsuspected adenocarcinoma within the first year after detection of HGD ("the hunt"). Of the 75 patients with HGD who remained without detectable cancer following the one year of intensive searching, 12 patients (16%) subsequently developed carcinoma during a mean surveillance period of 7.3 years. Eleven of the 12 patients who developed carcinoma were considered cured with surgical or ablation therapy. From these data, the authors concluded that BE-related HGD without detectable carcinoma follows a relatively benign course in the vast majority of patients. It is interesting that of the 1,099 patients with BE, 737 had LGD, a number that far exceeds that of any other previously published study. One experienced gastrointestinal pathologist interpreted all of the biopsy specimens over a 20-year period. Although the results of this study are provocative, additional prospective studies with long-term follow-up in patients with non-surgical management of HGD are required, a task that may be difficult to reproduce.

Natural History of Low-Grade Dysplasia
Much less is known about the natural history of LGD. One of the major detriments to determining the clinical significance of this diagnosis is the high degree of interobserver variability known to exist in establishing a diagnosis of LGD.54,55  Skacel et al studied a group of 25 patients with a diagnosis of LGD with follow-up information.60 The original diagnosis of LGD was rendered by ten different surgical pathologists at one institution, and all of these cases were subsequently re-reviewed in a blinded fashion by three experienced gastrointestinal pathologists. Seven patients (28%) with follow-up developed HGD (5 patients) or invasive carcinoma (2 patients), 2 to 43 months after the initial diagnosis of LGD. Interestingly, when at least two gastrointestinal pathologists agreed on the diagnosis, there was a significant association with progression (7 of 17 patients; 41%). When all three gastrointestinal pathologists agreed on a diagnosis of LGD, 4 of 5 patients (80%) progressed. In contrast, of the 8 patients with follow-up and no agreement among gastrointestinal pathologists for a diagnosis of LGD, none progressed. Thus, this study suggests that a consensus diagnosis of LGD among gastrointestinal pathologists is associated with an increased risk of progression from LGD to HGD or invasive carcinoma.

Management of Barrett's-related Dysplasia
The management of patients with Barrett's-related dysplasia is controversial, and varies from institution to institution. Given the paucity of prospective data on the natural history and time course of the dysplasia-carcinoma sequence, there is no standard way to manage these patients. At our institution, the current management plan is a modification of the recommended guidelines proposed by Reid et al.36  Once a diagnosis of BE is made, patients are followed with yearly endoscopy with biopsy. If a diagnosis of indefinite or LGD is rendered, patients are generally placed on anti-reflux therapy in order to reduce the intensity of inflammation and reactive epithelial changes that could be misinterpreted as dysplasia. Following anti-reflux therapy, our gastroenterologists generally repeat endoscopy with biopsy in 3-6 months. If the repeat biopsies are also negative, we repeat endoscopy with biopsy at 3-6 month intervals until two consecutive negative interpretations are encountered, followed by a return to yearly surveillance. However, if indefinite or LGD persists, we continue a program of 3-6 month surveillance until dysplasia progresses.

While the management of HGD is controversial, at our institution, we consider esophagectomy if a diagnosis of HGD is confirmed. Confirmation can be obtained either by review and agreement by an experienced gastrointestinal pathologist, or by immediate re-endoscopy and biopsy with a diagnosis of HGD.61  Given our relatively low mortality rate from esophagectomy (around 2%), we believe this procedure is indicated in operative candidates with HGD.

Adjunctive Techniques in Screening for Barrett's-related Dysplasia
Several adjunctive techniques have been proposed as having a possible role in the screening for dysplasia in patients with BE, given the limitations and imperfections of routine light microscopy. DNA content, as measured by flow cytometric methods, has been studied in the dysplasia-carcinoma sequence in patients with BE, the results of which have been conflicting. In 1987, Reid et al found an increased prevalence of DNA aneuploidy and elevated S-phase fraction with increasing severity of the histologic abnormality.62  In 1992, Reid et al prospectively studied 62 patients with BE by both histology and flow cytometry.35  Interestingly, 9 of 13 patients who had aneuploidy or increased G2/tetraploid populations in their initial biopsy specimens developed HGD or carcinoma, with a mean follow-up interval of 34 months. None of the 49 patients without aneuploidy or increased G2/tetraploid populations progressed to HGD or carcinoma. In a more recent prospective study by Reid et al,63  patients with negative, indefinite or LGD with neither aneuploidy nor increased 4N fraction had a 0% 5-year cumulative cancer incidence compared with 28% for those with either aneuploidy or increased 4N. Patients with baseline increased 4N, aneuploidy and HGD had 5-year cancer incidences of 56%, 43% and 59%, respectively. In contrast to the results obtained by Reid et al, Fennerty et al found discordance between flow cytometric abnormalities and dysplasia in patients with BE.64  Thus, further studies are necessary to explore the possibility of flow cytometry as a diagnostic adjunct in Barrett's-related dysplasia.

REFERENCES

  1. Spechler SJ, Goyal RK. Barrett's esophagus. N Engl J Med 1986;315:362-371.
  2. Collen MJ, Lewis JH, Benjamin SB. Gastric acid hypersecretion in refractory gastroesophageal reflux disease. Gastroenterology 1990;98:654-661.
  3. Dent J, Bremner CG, Collen MJ, et al. Working party report to the World Congresses of Gastroenterology, Sidney, 1990: Barrett's esophagus. J Gastroenterol Hepatol 1991;6:1-22.
  4. Mulholland MW, Reid BJ, Levine DS, et al. Elevated gastric acid secretion in patients with Barrett metaplastic epithelium. Dig Dis Sci 1989;34:1329-1335.
  5. Haggitt RC, Tryzelaar J, Ellis FH, et al. Adenocarcinoma complicating columnar epithelial-lined (Barrett's) esophagus. Am J Clin Pathol 1978;70:1-5.
  6. Haggitt RC. Adenocarcinoma in Barrett's esophagus: A new epidemic? Hum Pathol 1992;23:475?476.
  7. Blot WJ. Esophageal cancer trends and risk factors. Semin Oncol 1994;21:403-410.
  8. Bombeck CT, Dillard DH, Nyhus LM. Muscular anatomy of the gastroesophageal junction and role of phrenoesophageal ligament. Autopsy study of sphincter mechanism. Ann Surg 1966;164:643-654.
  9. Der R, Tsao-Wei DD, Demeester T, et al. Carditis. A manifestation of gastroesophageal reflux disease. Am J Surg Pathol 2001;25:245-252.
  10. Öberg S, Peters JH, DeMeester TR, et al. Inflammation and specialized intestinal metaplasia of cardiac mucosa is a manifestation of gastroesophageal reflux disease. Ann Surg 1997;226:522-532.
  11. Chandrasoma PT, Lokuhetty DM, Demeester TR, et al. Definition of histopathologic changes in gastroesophageal reflux disease. Am J Surg Pathol 2000;24:344-351.
  12. Owen DA. Stomach. In: Sternberg SS (ed). Histology for pathologists. New York, Raven Press, 1992, 533-545.
  13. Chandrasoma PT, Der R, Ma Y, et al. Histology of the gastroesophageal junction: an autopsy study. Am J Surg Pathol 2000;24:402-409.
  14. Kilgore S, Ormsby AH, Gramlich TL, et al. The gastric cardia: fact or fiction? Am J Gastroenterol 2000;95:921-924.
  15. Spechler SJ, Goyal RK. The columnar-lined esophagus, intestinal metaplasia and Norman Barrett. Gastroenterology 1996;110:614-621.
  16. Paull A, Trier JS, Dalton MD, et al. The histologic spectrum of Barrett's esophagus. N Engl J Med 1976;295:476-480.
  17. Haggitt RC. Barrett's esophagus, dysplasia and adenocarcinoma. Hum Pathol 1994;25:982-993.
  18. Weinstein WM, Ippoliti AF. The diagnosis of Barrett's esophagus. Goblets, goblets, goblets. Gastrointest Endosc 1996;44:91-94.
  19. Sampliner RE. Practice guidelines on the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 1998;93:1028-1031.
  20. Sharma P, Morales TG, Sampliner RE. Short segment Barrett's esophagus - the need for standardization of the definition and of endoscopic criteria. Am J Gastroenterol 1998;93:1033-1036.
  21. Weston AP, Krmpotich P, Makdisi WJ, et al. Short-segment Barrett's esophagus: clinical and histological features, associated endoscopic findings and association with gastric intestinal metaplasia. Am J Gastroenterol 1996;91:981-986.
  22. Offner FA, Lewin KJ, Weinstein WM. Metaplastic columnar cells in Barrett's esophagus: A common and neglected cell type. Hum Pathol 1996;27:885-889.
  23. Spechler SJ, Zeroogian JM, Antonioli DA, Wang HH, Goyal RK. Prevalence of metaplasia at the gastroesophageal junction. Lancet 1994;344:1533-1536.
  24. Johnston MH, Hammond AS, Laskin W, et al. The prevalence and clinical characteristics of short segments of specialized intestinal metaplasia in the distal esophagus on routine endoscopy. Am J Gastroenterol 1996;91:1507-1511.
  25. Nandukar S, Talley NJ, Martin CJ, et al. Short segment Barrett's esophagus: prevalence, diagnosis and associations. Gut 1997;40:710-715.
  26. Trudgill MJ, Suvarna SK, Kapur KC, Riley SA. Intestinal metaplasia at the squamocolumnar junction in patients attending for diagnostic gastroscopy. Gut 1997;41:585-589.
  27. Ormsby AH, Goldblum JR, Richter JE, et al. The sensitivity and specificity of histologic features in the diagnosis of Barrett's esophagus on routine endoscopic biopsy specimens. Am J Clin Pathol 1999;112:A533.
  28. Hirota WK, Loughney TN, Lazas DJ, et al. Specialized intestinal metaplasia, dysplasia and cancer of the esophagus and esophagogastric junction: prevalence and clinical data. Gastroenterology 1999;116:27-285.
  29. Morales TG, Sampliner RE, Bhattacharyya A. Intestinal metaplasia of the gastric cardia. Am J Gastroenterol 1997;92:414-418.
  30. Goldblum JR, Vicari JJ, Falk GW, et al. Inflammation and intestinal metaplasia of the gastric cardia: the role of gastroesophageal reflux and H. pylori infection. Gastroenterology 1998;114:633-639.
  31. Hackelsberger A, Gunther T, Schultze V, et al. Intestinal metaplasia at the gastroesophageal junction: Helicobacter pylori gastritis or gastro?esophageal reflux disease? Gut 1998;43:17?21.
  32. Sjogren RW, Johnson LF. Barrett's esophagus: A review. Am J Med 1983;74:3131-3140.
  33. Hamilton SR, Smith RRL. The relationship between columnar epithelial dysplasia and invasive adenocarcinoma arising in Barrett's esophagus. Am J Clin Pathol 1987;87:301-312.
  34. Lee RG. Dysplasia in Barrett's esophagus: A clinicopathologic study of six patients. Am J Surg Pathol 1985;9:845-852.
  35. Reid BJ, Blount PL, Rubin CE, et al. Predictors of progression to malignancy in Barrett's esophagus: Endoscopic, histologic and flow cytometric follow-up of a cohort. Gastroenterology 1992;102:1212-1219.
  36. Reid BJ, Weinstein WM, Lewin KJ, et al. Endoscopic biopsies diagnose high-grade dysplasia or early operable adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions. Gastroenterology 1988;94:81-90.
  37. Schmidt HG, Riddell RH, Wather B, et al. Dysplasia in Barrett's esophagus. J Cancer Res Clin Oncol 1985;110:145-152.
  38. Smith RRL, Hamilton SR, Boitnott JK, et al. The spectrum of carcinoma arising in Barrett's esophagus: A clinicopathologic study of 26 patients. Am J Surg Pathol 1984;8:562-573.
  39. Hameeteman W, Tytgat GNJ, Houthoff HJ, et al. Barrett's esophagus: Development of dysplasia and adenocarcinoma. Gastroenterology 1989;96:1249-1256.
  40. Schnell, TG, Sontag SJ, Chejfec G: Adenocarcinomas arising in tongues or short segments of Barrett's esophagus. Dig Dis Sci 1992;37:137-143.
  41. Menke-Pluymers MBE, Hop WCJ, Dees J, et al. Risk factors for the development of an adenocarcinoma in columnar-lined (Barrett) esophagus. Cancer 1993;72:1155-1158.
  42. Sharma P, Weston AP, Morales T, et al. Relative risk of dysplasia for patients with intestinal metaplasia in the distal oesophagus and in the gastric cardia. Gut 2000;46:9-13.
  43. Morales TG, Camargo E, Bhattacharyya A, et al. Long-term follow-up of intestinal metaplasia of the gastric cardia. Am J Gastroenterol 2000;95:1677-1680.
  44. Goldstein NS. Gastric cardia intestinal metaplasia: Biopsy follow-up of 85 patients. Mod Pathol 2000;13:1072-1079.
  45. Ormsby AH, Goldblum JR, Rice TW, et al. Cytokeratin subsets can reliably distinguish Barrett's esophagus from intestinal metaplasia of the stomach. Hum Pathol 1999;30:288-294.
  46. Ormsby AH, Vaezi MF, Richter JE, et al. Cytokeratin immunoreactivity patterns in the diagnosis of short-segment Barrett's esophagus. Gastroenterology 2000;119:683-690.
  47. Glickman JN, Wang H, Das KM, et al. Phenotype of Barrett's esophagus and intestinal metaplasia of the distal esophagus and gastroesophageal junction. An immunohistochemical study of cytokeratins 7 and 20, Das-1 and 45M1. Am J Surg Pathol 2001;25:87-94.
  48. Glickman JN, Ormsby AH, Gramlich T, et al. Interinstitutional variability in the interpretation of cytokeratin 7/20 staining patterns in Barrett's esophagus. Gastroenterology 2001;120 (abstr).
  49. Falk GW, Rice TW, Goldblum JR, et al. Jumbo biopsy forceps protocol still misses unsuspected cancer in Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc 1999;49:170-176.
  50. Riddell RH, Goldman H, Ransohoff DF, et al. Dysplasia in inflammatory bowel disease: Standardized classification with provisional clinical implications. Hum Pathol 1983;14:931-968.
  51. Goseki M, Koike M, Yoshida M. Histopathologic characteristics of early stage esophageal carcinoma. A comparative study with gastric carcinoma. Cancer 1992;69:1088-1093.
  52. Sabik JF, Rice TW, Goldblum JR, et al. Superficial esophageal carcinoma. Ann Thorac Surg 1995;60:896-902.
  53. Ormsby AH, Petras RE, Henricks WH, et al. Interobserver variation in the diagnosis of superficial adenocarcinoma in Barrett's esophagus. Mod Pathol 1998;11:386A.
  54. Reid BJ, Haggitt RC, Rubin CE, et al. Observer variation in the diagnosis of dysplasia in Barrett's esophagus. Hum Pathol 1988;19:166-178.
  55. Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis of dysplasia in Barrett's esophagus: a reaffirmation. Hum Pathol 2001;32:368-378.
  56. Rice TW, Falk GW, Achkar E, et al. Surgical management of high-grade dysplasia in Barrett's esophagus. Am J Gastroenterol 1993;88:1832-1836.
  57. Reid BJ, Blount PL, Feng Z, et al. Optimizing endoscopic biopsy detection of early cancers in Barrett's high-grade dysplasia. Am J Gastroenterol 2000;95:3089-3096.
  58. Weston AP, Sharma P, Topalovski M, et al. Long-term follow-up of Barrett's high-grade dysplasia. Am J Gastroenterol 2000;95:1888-1893.
  59. Schnell TG, Sontag SJ, Chejfec G, Aranha G, Metz A, O'Connell S, Seidel UJ, Sonnenberg A. Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology 2001;120:1607-1619.
  60. Skacel M, Petras RE, Gramlich TL, et al. The diagnosis of low-grade dysplasia in Barrett's esophagus and its implications for disease progression. Am J Gastroenterol 2000;95:3383-3387.
  61. Petras RE, Sivak MV, Rice TW. Barrett's esophagus: A review of the pathologist's role in diagnosis and management. Pathol Annu 1991;26:1-32.
  62. Reid BJ, Haggitt RC, Rubin CE, et al. Flow cytometry complements histology in detecting patients at risk for Barrett's adenocarcinoma. Gastroenterology 1987;93:1-11.
  63. Reid BJ, Levine DS, Longton G, et al. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets. Am J Gastroenterol 2000;95:1669-1676.
  64. Fennerty MB, Sampliner RE, Way D, et al. Discordance between flow cytometric abnormalities and dysplasia in Barrett's esophagus. Gastroenterology 1989;97:815-820.