Update on the diagnosis and treatment of Barrett esophagus and related neoplastic precursor lesions.
Abstract: * Context.--At present, Barrett esophagus is the most common cause of esophageal adenocarcinoma. In the past 20 years, the incidence of esophageal adenocarcinoma in white males has exceeded that of tumors of the colorectum, lung, prostate, and skin.

Objectives.--To (1) provide an evidence-based review of the diagnosis, classification, and histologic differentiation of Barrett esophagus from gastric carditis, (2) provide a summary of the key pathologic features of precursor lesions, such as dysplasia, and (3) evaluate adjunctive markers of dysplasia and predictive markers for the development of cancer. The natural history and risk of cancer in patients with Barrett esophagus is also reviewed.

Data Sources.--For this review, selected published peer reviewed articles were chosen from a search through PubMed between the years 1970 and 2007.

Conclusions.--The current definition of Barrett esophagus is partially flawed because not all cases are endoscopically recognizable, nongoblet epithelium is biologically intestinalized, and determination of the presence or absence of goblet cells is susceptible to sampling error. Differentiation of ultrashort segment Barrett esophagus from chronic gastric carditis can be accomplished, in a minority of cases, by evaluating for the presence or absence of histologic features that are known to be associated with Barrett esophagus. Dysplasia in Barrett esophagus begins in the crypt bases and then extends more superficially to include the upper portions of the crypts and surface epithelium. Low-and high-grade dysplasia are distinguished by the presence of marked cytologic and/or architectural abnormalities in the latter compared with the former. There are few, if any, reliable adjunctive diagnostic techniques that can help differentiate nondysplastic from dysplastic epithelium. However, a-methylacyl coenzyme A racemase staining has been shown to be useful in 2 separate studies. Both low- and high-grade dysplasia are progressive lesions, and in general, the extent of dysplasia, particularly low grade, is a strong risk factor for progression to carcinoma. Of all the biologic and genetic biomarkers studied to date, evaluation of DNA content is the most reliable and specific. The management of patients with dysplasia is variable among institutions and ranges from aggressive surveillance, endoscopic mucosal resection, mucosal ablation, or total esophagectomy.
Article Type: Report
Subject: Barrett's esophagus (Diagnosis)
Barrett's esophagus (Care and treatment)
Endoscopic surgery (Usage)
Endoscopy (Usage)
Author: Odze, Robert D.
Pub Date: 10/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: Oct, 2008 Source Volume: 132 Source Issue: 10
Topic: Event Code: 350 Product standards, safety, & recalls
Organization: Organization: American College of Gastroenterology
Geographic: Geographic Scope: United Kingdom; United States Geographic Code: 4EUUK United Kingdom; 1USA United States
Accession Number: 230246849
Full Text: In the past 20 years, the incidence of esophageal adenocarcinoma in white males has exceeded that of tumors of the colorectum, lung, prostate, and skin (melanoma). (1,2) In the United Kingdom and in whites in the United States, adenocarcinoma is more frequent than squamous cell carcinoma of the esophagus. (3) The increase in the annual incidence rate in men is between 10% and 20% in Europe and North America. (3-5) Most adenocarcinomas of the esophagus develop on a background of Barrett esophagus (BE), which in turn is caused by chronic gastroesophageal reflux disease (GERD). (6) Both GERD and BE are relatively common disorders. (7,8) Symptomatic GERD affects approximately 20% of the adult US population, and BE is diagnosed in about 5% of patients who have undergone upper endoscopy for GERD. (9,10) The absolute risk of BE patients for cancer is roughly 0.5% per year. (1,11)

In general, adenocarcinoma in BE develops through a GERD-metaplasia-dysplasia-carcinoma sequence. (12,13) Due to the recent widespread use of endoscopy, pathologists are increasingly exposed to biopsy specimens from patients with GERD, BE, and associated dysplasia. Thus, our role as pathologists is to diagnose BE and related neoplastic precursor lesions, and to help guide patient management. This review focuses on recent advances regarding the diagnosis, differential diagnosis, pathogenesis, natural history, and risk assessment of malignancy in BE.

DIAGNOSIS AND CLASSIFICATION OF BE

The American College of Gastroenterology defines BE as endoscopically recognizable columnar metaplasia of the esophageal mucosa that is confirmed to have intestinal metaplasia (defined by the presence of goblet cells) in mucosal biopsy specimens. (14) By definition, this disease does not include patients who have intestinal metaplasia of the gastric cardia. Traditionally, BE is separated into long-segment, short-segment, or ultrashort-segment types depending on the length (>3 cm, 1-3 cm, or <1 cm, respectively) of involved mucosa. (14) However, the biologic significance of this classification system remains unclear. Although length of BE is probably related to cancer risk, even this issue is controversial. (15-17) Recently, an alternative endoscopic classification for BE was proposed by Sharma et al (18) termed the Prague C & M Criteria. This system classifies BE based on both the length of circumferential involvement and the maximal proximal extent of columnar mucosa in the esophagus, and has been shown to increase reproducibility for assessment of BE, but awaits validation by other investigators.

As mentioned previously, our clinical colleagues have defined BE by the presence of "intestinal metaplasia" in the esophagus. This is based primarily on the assumption that this epithelium is the type at highest risk for neoplastic progression. (19,20) However, there are several weaknesses of this definition. First, it is now well recognized that the background nongoblet columnar epithelium, even in patients without goblet cell metaplasia, shows physiologic properties of "intestinal" differentiation, such as expression of the intestinal transcription factor CDX-2, He par-1, villin, DAS-1, and MUC-2. (21-25) In addition, nongob let epithelium in BE also shows cells with a mixed gastric and intestinal phenotype. (21) Second, cancer may also develop in goblet cell poor, or rarely even nongoblet, esophageal columnar epithelium. (26,27) In fact, both anecdotal evidence and preliminary studies have suggested that neoplastic progression in BE is associated with loss of goblet cell differentiation. In 1 recent study published only in abstract form of 151 BE patients, 63 of whom developed cancer, goblet cell density in nondysplastic epithelium from BE patients without dysplasia was significantly higher than in nondysplastic epithelium from patients with dysplasia. (28) In fact, in that study, goblet cell density in nondysplastic crypts was not found to be a useful predictor of cancer risk. The relationship between density of goblet cell metaplasia and cancer risk has never been defined specifically regarding whether this is an absolute (all or none) or a continuous (linear) association. Although it seems logical that an increase in the density of goblet cells is related to an increase in the risk of neoplastic progression, this hypothesis has never been tested objectively. Third, the chance of detecting goblet cells in mucosal biopsies from the esophagus in patients suspected of having BE is essentially proportional to the length of BE and is subject to sampling error. (29-31) In a study by Oberg et al, (31) the prevalence of goblet cell metaplasia was 30.5% in patients with 1 to 2 cm of columnar-lined esophagus compared with nearly 90% in patients with BE segments longer than 6 cm. Not surprisingly, the likelihood of detecting goblet cells increases with both the number of biopsies and also the location of the biopsy. In fact, biopsies obtained from the neo-squamocolumnar junction shows a higher rate of detection of goblet cell metaplasia compared with biopsies obtained from distal areas of BE. In 1 study of 296 endoscopies in 125 BE patients, goblet cells were detected in 68% of endoscopies in which 8 biopsies were obtained compared with only 35% in which of only 4 biopsies were analyzed. (30)

DIFFERENTIATION OF ULTRASHORT SEGMENT BE FROM CHRONIC GASTRIC CARDITIS

Ultrashort BE and chronic carditis with intestinal metaplasia, the latter most often due to Helicobacter pylori infection, are common disorders that have a different etiology, natural history, and risk of malignancy. (21,32,33) For instance, patients with ultrashort BE are more commonly males compared with females and are typically older in age. Most patients develop ultrashort BE as a result of GERD, and the BE typically represents a squamous-to-columnar metaplastic transition (rather than a columnar-to-columnar transition). In addition, this patient group has a higher risk for cancer and is therefore treated with acid suppression, surveillance, or surgery rather than antibiotics. (21) Unfortunately, these 2 conditions are often difficult to differentiate from each other based on clinical and endoscopic methods due, in part, to difficulties in identifying anatomic landmarks related to the gastroesophageal junction (GEJ). (34) Thus, it has become incumbent on pathologists to help differentiate these 2 conditions based on biopsies from the "GEJ region." Clinical features in favor of ultra-short BE include the presence of GERD symptoms and, if available, appropriate manometric and luminal pH probe findings. The presence of a hiatus hernia is also strongly associated with BE. Endoscopically, the gross appearance of the distal esophagus, and the relationship of the squamocolumnar junction (Z-line) to the anatomic GEJ, which is defined as the most proximal limit of the gastric folds, is also helpful in separating these conditions. Ultrashort BE is characterized by a slightly irregular, proximally located, Z-line relative to the GEJ, and/or the appearance of short tongues of gastric-type mucosa that extend into the distal esophagus.

Pathologically, a recent study by Srivastava et al (35) evaluated the utility of a variety of morphologic features in distinguishing ultrashort BE from gastric carditis with intestinal metaplasia (Table). They found that the presence of squamous epithelium overlying crypts with intestinal metaplasia, hybrid glands, and/or esophageal mucosal glands, or their ducts, were 100% specific for ultrashort BE in biopsies obtained from the GEJ region. In addition, significant crypt disarray and atrophy, diffuse incomplete intestinal metaplasia, and the presence of multilayered epithelium were highly associated with ultrashort BE versus carditis with intestinal metaplasia. When available, the pathologic features in the squamous epithelium of the esophagus and in the distal stomach are also helpful. Most cases of H pylori-associated carditis also show H pylori antritis. In contrast, active reflux esophagitis combined with the finding of a normal gastric antrum and corpus is strong evidence in favor of BE. Furthermore, biopsies from the GEJ region in cases of ultrashort BE also tend to show a higher quantity of eosinophils in the lamina propria and epithelium in contrast to prominent plasma cells, neutrophils, and reactive lymphoid aggregates in cardia biopsies with H pylori infection. (36)

The utility of histochemical stains is more controversial. In 1 study by Chen et al, (37) high iron diamine positivity, indicating the presence of sulfomucins, in nongoblet columnar cells in biopsies from the GEJ region has been shown to be highly suggestive of columnar metaplasia of the distal esophagus. Recently, immunohistochemical expression of combined Muc-1 and Muc-6 has been shown to be highly associated with goblet cell metaplasia related to BE, but not with that associated with chronic H pylori carditis. (38) Finally, although some investigators have suggested that a Barrett cytokeratin (CK) 7/20 staining pattern in biopsies from the distal esophagus or GEJ is highly suggestive of BE, others have not been able to confirm these findings and instead have shown that the CK7/20 staining profile in biopsies from this region are nonspecific. (33,39-42) Sixteen percent to 90% of cardia biopsies with intestinal metaplasia were shown to express a Barrett CK7/20 staining pattern in other biopsy studies, such as those by Glickman et al (40) and El-Zimaity and Graham. (42) A Barrett CK7/20 staining pattern is defined as diffuse strong CK7 staining, combined with superficial CK20 staining, of the intestinalized columnar epithelium.

PATHOGENESIS OF BE

The pathogenesis of BE, particularly with regard to the cell of origin, is poorly understood. (21,43) It is widely accepted that chronic GERD leads to inflammation and ulceration of the esophageal squamous mucosa, which if persistent and recurrent, leads to columnar metaplasia and eventually to "intestinal" metaplasia. Major risk factors for the development of this condition include chronic GERD and the presence of a hiatus hernia. (1) Although controversial, other reported risk factors include obesity, white ethnicity, alcohol consumption, tobacco use, duodenal-gastric reflux, delayed esophageal acid clearance, low resting pressure of the lower esophageal sphincter, and use of anticholinergic medications.1 Studies have confirmed that squamous epithelium converts initially to columnar epithelium morphologically similar to the gastric cardia, composed of mucinous columnar epithelium with underlying mucous glands or mixed mucous/oxyntic glands, prior to the development of goblet cells. More controversial, though, is the precise cell of origin of BE. (21,44,45) Possible primary sites of origin include the basal layer of the esophageal epithelium, the mucosal and/or submucosal glands and their respective ducts, or the gastric cardia. More recently, there is in vitro and experimental evidence to support the possibility that pluripotent stem cells may be derived from either undifferentiated mesenchymal cells in the lamina propria or the bone marrow. (46,47) Interestingly, several animal studies have provided strong evidence that the cell of origin of BE probably resides in the esophagus rather than the proximal stomach. (48,49) For example, both Gillen et al (48) and Lietal (49) showed that columnar reepithelization of the esophagus occurs even in the presence of physical barriers to proximal growth of the gastric cardia mucosa in animal experiments.

There is also morphologic and experimental evidence to suggest that the esophageal mucosal gland ducts harbor stem cells capable of differentiating into columnar epithelium. (50,51) Evidence in favor of this theory stems from both morphology and cytochemical studies. There is also accumulating evidence that the squamous-to-columnar cell metaplastic sequence occurs through an intermediate, or transitional, phase characterized by the presence of epithelium that shows combined squamous and columnar features, termed multilayered epithelium (51,52) (Figure 1). For instance, multilayered epithelium has been shown to express a similar mucin and cytokeratin profile to that of fully developed columnar metaplasia in BE and also shows a high capacity for cell proliferation, differentiation, and expression of intestinal transcription factors. (51) In other retrospective and prospective studies, the presence of multilayered epithelium was strongly associated with GERD-induced inflammation of the GEJ region and was nearly 100% specific for BE. (52,53) Thus, the clinical significance of multilayered epithelium for pathologists is related to the fact that its identification in a mucosal biopsy specimen from the GEJ region or distal esophagus helps define the columnar epithelium in the sample as metaplastic in origin.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

DYSPLASIA IN BE

Similar to dysplasia in other locations of the gastrointestinal tract, dysplasia in BE is defined as unequivocal neoplastic epithelium confined to the basement membrane. (54) It is classified as negative, indefinite, or positive (low or high grade) according to a classification system developed initially for dysplasia in inflammatory bowel disease. (55) At present, dysplasia is the best marker of an increased risk of malignancy in BE. Although most patients with BE who develop cancer follow a linear progression from metaplasia to low- and then high-grade dysplasia, some patients may develop cancer directly from either metaplasia or low-grade dysplasia, without intervening high-grade dysplasia. In a study by Schnell et al, (56) 10 patients with BE progressed from low-grade dysplasia directly to adenocarcinoma without intervening high-grade dysplasia.

Many pathologists in Europe and Asia prefer the Vienna classification system of grading dysplasia in BE, which uses the term non-invasive neoplasia instead of low-or high-grade dysplasia, includes a category for noninvasive carcinoma (carcinoma in situ), and also uses the category of "suspicious for" invasive carcinoma for biopsies that show equivocal features of tissue invasion. (57) Otherwise, these 2 dysplasia classification systems are similar.

BE, NEGATIVE FOR DYSPLASIA

There is a growing body of evidence to suggest that morphologically nondysplastic BE represents an early form of "neoplasia" the latter of which is often defined as a new growth that exceeds and is uncoordinated compared with normal tissues, persists after cessation of stimuli, and is composed of a clone of cells with loss of cell cycle regulation. (58-60) Barrett esophagus has been shown to be hyperproliferative, clonal, and progressive and does not normally regress without intervention. (61,62) There is both architectural and cytologic evidence that nondysplastic BE differs markedly from "normal" intestinal mucosa. For instance, established nondysplastic BE typically shows crypt budding, atrophy, branching, increased mitotic activity, dystrophic goblet cells, mucin depletion, and nuclear hyperchromaticity (54) (Figure 2). Molecular aberrations in the p16 gene are detected in approximately 90% of nondysplastic BE and these changes frequently show clonal expansion throughout the Barrett segment. (61,63) Clonal cytogenetic abnormalities, both numerical and structural, also occur in nondysplastic BE. (64) In 1 study using high-fidelity image cytometry to measure aneuploidy, 69% of BE cases showed at least a mild degree of aneuploidy. (65) Furthermore, CDX and p53 mutations have been shown to develop at an early phase of columnar metaplasia prior to the onset of morphologic dysplasia. (66) Consequently, the epithelium in nondysplastic BE often shows a variable degree of "regenerative" changes that may appear "atypical" to some.

BE, INDEFINITE FOR DYSPLASIA

At the severe end of the regeneration spectrum, the degree of cytologic atypia may overlap with true dysplasia, which is particularly apparent in instances in which significant inflammation/ulceration is present in the biopsy specimen. (54) Thus, for biopsies in which a definite distinction between regeneration and dysplasia cannot be made with certainty, an interim diagnosis of "indefinite for dysplasia" is usually applied. This term is also used for biopsies in which an accurate diagnosis is difficult due to technical issues, such as tangental or thick-tissue sectioning, poor orientation, lack of surface epithelium, or marked cautery artifact. It is this category of diagnostic uncertainty that, not surprisingly, has led to a substantial degree of interobserver variability in the diagnosis of dysplasia, among both general and specialty gastrointestinal pathologists. (67-69) From a pathologist's perspective, in biopsy specimens that show cytologic atypia in the form of hyperchromatic nuclei, pseudostratification, increased mitoses and mucin depletion, the lack of an abrupt transition from atypical to nonatypical epithelium, and the presence of surface maturation, combined with a lack of significant nuclear pleomorphism, atypical mitoses, and loss of cell polarity, are helpful features in distinguishing regeneration from true dysplasia. In fact, inflammation-induced atypical changes are often most pronounced at the neo-squamocolumnar junction, an area in which pathologists should approach with caution when evaluating dysplasia.

BE, POSITIVE FOR DYSPLASIA

There are 2 general histologic types of dysplasia in BE referred to as adenoma-like or non-adenoma-like. (54) Little is known regarding the biologic characteristics and natural history of non-adenoma-like dysplasia. Adenoma-like dysplasia resembles, in most instances, inflammatory bowel disease-related dysplasia. It is important to recognize that neoplastic changes in BE develop and progress on a morphologic continuum and, thus, does not follow clearly definable steps, which is a limitation when pathologists try to compartmentalize dysplasia into discrete grades. Nevertheless, by convention, low-grade dysplasia is defined as epithelium that shows relatively preserved crypt architecture and cytologically atypical nuclei limited, for the most part, to the basal half of the cell cytoplasm (Figure 3). The nuclei in low-grade dysplasia are typically hyperchromatic, elongated, show a clumped chromatin pattern, either with or without multiple nucleoli, and an irregular contour. Other features include dysplastic goblet cells, mucin depletion, increased mitoses, both typical and atypical, slight loss of cell polarity, and often no or only mild pleomorphism. With neoplastic progression to highgrade dysplasia, the degree of cytologic and/or architectural complexity increases to the point where there may be branching complex crypts, back-to-back gland formation, or villiform configuration of the surface epithelium (Figure 3, B). Thus, high-grade dysplasia is defined by the presence of increased crypt complexity, crowding, irregularity, and branching and cytologically by more pronounced nuclear stratification, loss of cell polarity, pleomorphism, and mitotic activity. Unfortunately, there are no defined guidelines regarding the minimum number of high-grade dysplastic crypts necessary to upgrade a diagnosis of low-grade dysplasia to high-grade dysplasia in any particular biopsy specimen. Nevertheless, a common sense approach might be to include both the grade and extent (in percentages) of both low- and high-grade dysplasia in pathology reports.

There is recent morphologic, immunohistochemical, and molecular evidence to suggest that dysplasia begins initially in the crypt bases and progresses, with time, to in volve the full length of the crypts and surface epithelium.70 Thus, there are instances in which dysplasia may be visible only in the crypt bases, whereas the upper crypts and/or surface epithelium show evidence of surface maturation, the latter of which is generally regarded as a nondysplastic feature. Morphologically, crypt dysplasia shows all of the cytologic features of low-grade dysplasia, but is limited to the bases of the crypts in biopsies without active inflammation (Figure 4, A and B). The surface epithelium in these cases may show slight stratification, but the nuclei are typically smaller in size and the cytoplasm shows more abundant mucin compared with the crypt cells. In a recent study by Lomo et al (70) of 15 patients with basal crypt dysplasia, 47% of cases were associated with full crypt dysplasia in other portions of the esophagus from the same patients and showed a higher MIB-1 proliferation rate, p53 positivity, and a higher prevalence rate of molecular abnormalities, such as 9p loss of heterozygosity, 17p loss of heterozygosity, increased 4n fraction, and aneuploidy, compared with BE cases without basal crypt dysplasia. Furthermore, in a study that evaluated DNA content in the superficial versus the basal portion of crypts in patients with BE and dysplasia by high-fidelity image cytometry, the basal portions of crypts in areas of basal crypt dysplasia showed aneuploidy in 50% of cases, which was similar to the basal crypts in cases of full crypt low-grade dysplasia. (71) An analysis of the superficial portions of the crypts showed a diploid DNA pattern in cases of basal crypt dysplasia compared with aneuploidy in cases of traditional full crypt dysplasia. The natural history and risk of malignancy of patients with basal crypt dysplasia requires further investigation.

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

ADENOCARCINOMA IN BE

Adenocarcinoma is defined as neoplastic epithelium that has invaded beyond the basement membrane into the surrounding lamina propria or muscularis mucosa (intramucosal adenocarcinoma) or into the submucosa (submucosal invasive adenocarcinoma). Due to the presence of lymphatics and blood vessels in the esophageal lamina propria, adenocarcinomas, even those limited to the mucosa, may result in lymph node metastasis in a small proportion of cases (5%). (72) Intramucosal or submucosal adenocarcinomas should be diagnosed when individual, or small clusters of, cells show clear penetration into the lamina propria, or when the crypt architecture and contours have deviated significantly from what one normally sees in nondysplastic BE. Intraluminal necrosis in a biopsy with high-grade dysplastic glands often is a sign of synchronous intramucosal, or invasive, adenocarcinoma. (54,73) Unfortunately, distinction between high-grade dysplasia and intramucosal adenocarcinoma is often difficult and, as a result, suffers from a significant degree of interobserver variability. (73)

ADJUNCTIVE MARKERS OF DYSPLASIA

Until recently, there have been few, if any, reliable adjunctive diagnostic techniques helpful in differentiating nondysplastic from dysplastic epithelium in mucosal biopsies from the esophagus. (54) Although many types of histochemical biomarkers have been evaluated, such as K167, PCNA, cyclin D1, and p53, none have shown to be clinically useful. (74-76) For example, although previous studies have shown that the extent and distribution of Ki-67 staining correlates reasonably well with increasing grades of dysplasia, unfortunately, regenerating epithelium can also demonstrate increased proliferation, which in some instances can approach that seen in high-grade dysplasia. (74) Similarly, although the frequency of positive immunostaining for p53 has been shown to be proportional to the grade of dysplasia and in fact may have predictive value in assessing risk of malignancy in patients with BE, unfortunately, p53 may be detected in up to 10% of biopsies that are histologically negative for dysplasia and its immunostaining has a high rate of both false positives and false negatives. (77,78) Thus, p53 immunostaining is not advocated as a routine marker for diagnostic use in BE.

Recently, Dorer and Odze (79) and another study by Lisovsky et al (80) reported considerable diagnostic utility of a-methylacyl coenzyme A racemase immunostaining in detecting dysplastic epithelium in BE. In the study by Dorer and Odze, (79) 38% of low-grade dysplasia cases and 81% of high-grade dysplasia cases showed diffuse strong positivity for [alpha]-methylacyl coenzyme A racemase compared with 0% of the BE cases considered negative for dysplasia. Thus, due to the low sensitivity, but high specificity, a positive result may be helpful to establish a diagnosis of "dysplasia" in diagnostically difficult cases, but the absence of staining does not necessarily rule out the fact that the atypical focus actually represents true dysplasia.

NATURAL HISTORY AND RISK OF CANCER

High-grade dysplasia is associated with synchronous or metachronous adenocarcinoma in up to 59% of cases. (56,81,82) The incidence of adenocarcinoma in a resection specimen from a patient with high-grade dysplasia diagnosed on a prior biopsy sample is highly related to the presence or absence of a nodule, ulcer, or mass lesion. (83,84) Patients with flat endoscopically undetectable high-grade dysplasia have a much lower incidence of synchronous adenocarcinoma compared with those who have an endoscopically detectable lesion. In 1 study, the presence of a mucosal nodule in association with high-grade dysplasia increased the cancer risk by a factor of 2.5. (83)

The risk of metachronous adenocarcinoma is also dependent on whether high-grade dysplasia is diagnosed as a "prevalent" or "incident" finding. For example, in a prospective study by Reid et al, (82) the 5-year risk of cancer for patients with prevalent high-grade dysplasia was 59% compared with only 31% for patients with incident highgrade dysplasia.

The natural history of low-grade dysplasia is more controversial, particularly because there is a higher degree of interobserver variability in establishing this diagnosis, even among experienced gastrointestinal pathologists.67,85 Some studies show a progression rate from 2% to 6%, which in some instances is lower than the "regression" rate that approaches 75% in some studies. (56,86-88) More recent studies show that the risk of progression to highgrade dysplasia, or cancer, ranges from 30% to 80%, particularly in studies in which multiple pathologists had agreed on the initial diagnosis. (89-91) In a recent study by Srivastava et al (89) in which 3 gastrointestinal pathologists agreed on all diagnoses of low- or high-grade dysplasia in biopsies from 77 BE patients, 45% of those with a maximum diagnosis of low-grade dysplasia progressed to adenocarcinoma in the follow-up interval. In 1 series, 73% of patients with low-grade dysplasia had no evidence of dysplasia in any of their follow-up endoscopies; it is not always possible to rule out sampling error in these circumstances. (90) As mentioned previously, in some long-term surveillance studies, low-grade dysplasia progressed directly to adenocarcinoma without showing interval biopsies with high-grade dysplasia.

FACTORS AFFECTING FATE (AND DETECTION) OF DYSPLASIA

There are many endoscopic and pathologic factors that may affect the outcome results of patients with low- or high-grade dysplasia. Endoscopic factors include the number of biopsies, frequency of surveillance endoscopy, interfering factors such as the presence of a polyp, stricture, nodule, or ulcer, and prevalent versus incident dysplasia. Pathologic factors include correct interpretation (interobserver variability), the growth pattern of dysplasia (ie, flat vs elevated), and more recently, the extent of dysplasia. For instance, in a case-control study of 44 BE patients who progressed to cancer during the course of endoscopic surveillance, versus 33 who did not, an objective extensive quantitation analysis of crypts from patients' baseline endoscopic biopsies showed that both the mean number of dysplastic crypts (both low- and high-grade combined), and the mean proportion of dysplastic crypts, were highly significantly associated with risk of progression to cancer. (89) Most interestingly, in that study, the mean number and proportion of low-grade dysplastic crypts were more significantly associated with cancer risk than the extent of high-grade dysplasia. Two other less comprehensive studies that evaluated only the extent of high-grade dysplasia in mucosal biopsies, defined by different criteria, as a risk factor for adenocarcinoma, showed disparate results. (83,92) One showed a strong relationship with cancer and the other did not. Clearly, further studies are needed to determine the clinical relevance of the extent of dysplasia as a risk factor for cancer in patients with BE, prior to institution of specific management guidelines.

ADJUNCTIVE TECHNIQUES IN ASSESSING RISK OF MALIGNANCY IN BE

Many biologic and genetic biomarkers have been studied in BE such as markers of proliferation, DNA content, genetic mutations, growth factors, and apoptosis inhibitors. (82,93-97) Few, if any, have been validated as markers of risk of cancer in phase 3 or 4 prospective trials. (97) In fact, aside from morphologic evaluation of dysplasia, only evaluation of DNA content by flow cytometry has shown consistent results as a strong predictor of carcinoma in phase 4 trials. In 1 study, 9 of 13 patients who had either aneuploidy or increased G2/tetraploid cellular populations in their initial mucosal biopsy developed high-grade dysplasia or carcinoma within 34 months; however, none of 49 patients without these alterations progressed. (93) p53 immunoexpression has been evaluated in phase 3 trials but shows a high degree of false-positive and false-negative staining. Increased p53 immunoexpression and loss of heterozygosity of 9p and 17p are frequent early events in the metaplasia-to-dysplasia sequence, and some preliminary studies suggest that these tests may be helpful as markers of increased risk of progression to high-grade dysplasia and carcinoma in BE. (98,99) A detailed review of non-morphology-based biomarkers in BE is beyond the scope of this review article. The interested reader is referred to an article by McManus et al (100) for more details.

MANAGEMENT

The management of patients with BE, particularly those with dysplasia, is controversial, varies significantly between various institutions, and is based heavily on the level of expertise of the treating physician. (101-103) Although randomized prospective controlled trials comparing surveillance with other methods of treatment for patients with dysplasia in BE have not been performed, endoscopic surveillance has become the standard method of management of patients with BE (negative, indefinite, or lowgrade dysplasia) based primarily on the fact that several studies have shown a higher 5-year survival rate, and an earlier stage of detection of cancer, in patients who have had their tumor detected by surveillance endoscopy compared with those who have not. (104-106) Furthermore, the method of treatment of patients with BE and neoplastic precursor lesions is also very much individualized depending on a number of variables such as the extent of dysplasia, presence or absence of mucosal lesions, patient age, comorbidities, and length of BE, among others. (107)

It is generally agreed on by most authorities that patients with chronic GERD symptoms should have a screening endoscopy, with biopsies, to determine the presence or absence of dysplasia, and if none is detected on 2 successive endoscopies, then 3-year surveillance intervals are recommended. The treatment of BE patients with lowgrade dysplasia, particularly if unifocal, is generally managed by repeat endoscopy with annual surveillance until no dysplasia is detected. The management of patients with high-grade dysplasia is more controversial and variable. (107,108) Some centers manage patients with high-grade dysplasia with an aggressive 3-month interval biopsy surveillance protocol (composed of stepwise 4-quadrant biopsies every 1-2 cm of BE mucosa using jumbo biopsy forceps), whereas others recommend surgical intervention by either endoscopic mucosal resection or esophagectomy. Although beyond the scope of this review, a number of nonsurgical ablative techniques, such as radiofrequency, photodynamic therapy, cryotherapy, and argon plasma coagulation, have become viable options for treating patients with dysplasia. (109,110) For an excellent summary of nonsurgical ablative techniques available for patients with BE, the reader is referred to an article by Johnston. (111) Nevertheless, surgical intervention, or endoscopic mucosal resection, should be strongly considered in patients with multifocal high-grade dysplasia or an elevated lesion. Of course, esophagectomy, performed at high-volume institutions with particular expertise in this area, remains a reasonable strategy in surgically fit patients with recurrent diffuse high-grade dysplasia. Nevertheless, the precise threshold for surgical intervention needs to be individualized particularly if the patient is being treated at a low-volume institute where the morbidity and mortality rates from esophagectomy are significantly higher.

Accepted for publication March 10, 2008.

References

(1.) Wild CP, Hardle LJ. Reflux, Barrett's oesophagus and adenocarcinoma: burning questions. Cancer. 2003;3:676-684.

(2.) van SandickJW, van Lanschot JJB, Tygat GNJ, Offerhaus GJA, Obertop H. Barrett's oesophagus and adenocarcinoma: an overview of epidemiologic, conceptual and clinical issues. Scand J Gastroenterol. 2001;35:51-60.

(3.) Vizcaino AP, Moreno V, Lambert R, Perkin DM. Time trends incidence of both major histologic types of esophageal carcinomas in selected countries, 1973-1995. Int J Cancer. 2002;99:860-868.

(4.) Devesa SS, Blot WJ, Fraumeni JF. Changing patterns in the incidence of esophageal and gastric carcinomas in the United States. Cancer. 1988;3:2049 2053.

(5.) Botterweck AAM, Schouten LJ, Volovics A, et al. Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries. Int J Epidemiol. 2000;29:645-654.

(6.) Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastroenterology. 2004;127:310-330.

(7.) Gerson LB, Shelter K, Triadafilopoulos G. Prevalence of Barrett's esophagus in asymptomatic individuals. Gastroenterology. 2002;123:461-467.

(8.) Rex DK, Cummings O'W, Shaw M, et al. Screening for Barrett's esophagus in colonoscopy patients with and without heartburn. Gastroenterology. 2003;125: 1670-1677.

(9.) Paulson TG, Reid BJ. Focus on Barrett's esophagus and esophageal adenocarcinoma. Cancer Cell. 2004;6(1):11-16.

(10.) Ormsby AH, Kilgore SP, Goldblum JR, Richter JE, Rice TW, Gramlich TL. The location and frequency of intestinal metaplasia at the esophagogastric junction in 223 consecutive autopsies: implications for patient treatment and preventative strategies in Barrett's esophagus. Mod Pathol. 2000;13:614-620.

(11.) Souza RF, Spechler SJ. Concepts in the prevention of adenocarcinoma of the distal esophagus and proximal stomach. CA Cancer J Clin. 2005;55:334-351.

(12.) Hameetemen W, Tytgat GNJ, Houthoff HJ, van den Tweel JG. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology. 1989;96:1246-1256.

(13.) Hirota WK, Loughney TN, Lazas DJ, Maydonovitch CL, Rholl V, Wong RK. Specialized intestinal metaplasia, dysplasia and cancer of the esophagus and esophagogastric junction: prevalence and clinical data. Gastroenterology. 1999; 116:277-285.

(14.) Wang KK, Sampliner RE; Practice Parameters Committee of the American College of Gastroenterology. Updated guidelines 2008 for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am J Gastroenterol. 2008;103:788 797.

(15.) Gopal DV, Lieberman DA, Margaret N, et al. Risk factors for dysplasia in patients with Barrett's esophagus (BE): results from a multicenter consortium. Dig Dis Sci. 2003;48:1537-1541.

(16.) Avidan B, Sonnenberg A, Schnell TG, Chejfec G, Metz A, Sontag SJ. Hiatal hernia size, Barrett's length, and severity of acid reflux are all risk factors for esophageal adenocarcinoma. Am J Gastroenterol. 2002;97:1930-1936.

(17.) Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS. Predictors of progression to malignancy in Barrett's esophagus: endoscopic histologic and flow cytometry follow-up of a cohort. Gastroenterology. 1 992;102: 1212-1219.

(18.) Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett's esophagus: the Prague C & M Criteria. Gastroenterology. 2006;131:1392-1399.

(19.) Paraf F, Flejou JF, Pignon JP, et al. Surgical pathology of adenocarcinoma arising in Barrett's esophagus: analysis of 67 cases. Am J Surg Pathol. 1995;19: 183-191.

(20.) Smith RR, 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;8:563-573.

(21.) Odze RD. Unraveling the mystery of the gastroesophageal junction: a pathologist's perspective. Am J Gastroenterol. 2005;100:1853-1867.

(22.) Philips RW, Frierson HF, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am J Surg Pathol. 2003;27:1442-1447.

(23.) Chu PG, Ishizawa S, Wu E, et al. Hepatocyte antigen as a marker of hepatocellular carcinoma: an immunohistochemical comparison to CEA, CD10 and AFP. Am J Surg Pathol. 2002;26:978-988.

(24.) Freund JN, Domon-Dell C, Kedinger M, et al. Cdx1 and Cdx2 homeobox genes in the intestine. Biochem Cell Biol. 1998;7:957-969.

(25.) Glickman JN, Shahsafaei A, Odze RD. Mucin core peptide expression can help differentiate Barrett's esophagus from intestinal metaplasia of the stomach. Am J Surg Pathol. 2003;27:1357-1365.

(26.) Cameron AJ, Souto EO, Smyrk TC. Small adenocarcinomas of the esophagogastric junction: association with intestinal metaplasia and dysplasia. Am J Gastroenterol. 2002;97:1375-1380.

(27.) Cabrera RA, Chaves P, Crespo M, et al. Adenocarcinoma of the esophagogastric junction: could the characteristics of adjacent intestinal metaplasia help in the understanding of biopathogenesis. Dis Esophagus. 2002;15:287-289.

(28.) Srivastava A, Hornick JL, Li X, et al. Loss of goblet cell differentiation occurs with the progression of dysplasia in Barrett's esophagus. Gastroenterology. 2006;130(suppl 2):264A.

(29.) Jones TF, Sharma P, Daaboul B, et al. Yield of intestinal metaplasia in patients with suspected short-segment Barrett's esophagus (SSBE) on repeat endoscopy. Dig Dis Sci. 2002;47:2108-2111.

(30.) Harrison R, Perry I, Haddadin W, et al. Detection of intestinal metaplasia in Barrett's esophagus: an observational comparator study suggests the need for a minimum of eight biopsies. Am J Gastroenterol. 2007;102:115-1161.

(31.) Oberg S, Johansson J, Wenner J, et al. Endoscopic surveillance of columnar-lined esophagus: frequency of intestinal metaplasia detection and impact of antireflux surgery. Ann Surg. 2001;234:619-626.

(32.) Odze R. Cytokerin 7/20 immunostaining: Barrett's oesophagus or gastric intestinal metaplasia? Lancet. 2002;33:1711-1713.

(33.) Goldblum JR. The significance and etiology of intestinal metaplasia of the esophagogastric junction. Ann Diag Pathol. 2002;61(1):67-73.

(34.) Spechler SJ. The role of gastric carditis in metaplasia and neoplasia at the gastroesophageal junction. Gastroenterology. 1 999;1 17:21 8-228.

(35.) Srivastava A, Odze RD, Lauwers G, Redston M, Antonioli D, Glickman JN. Morphological features are useful in distinguishing Barrett's esophagus from carditis with intestinal metaplasia. Am J Surg Pathol. 2007;31:1733-1741.

(36.) Wieczorek T, Wang H, Antonioli D, Glickman J, Odze R. Pathologic features of reflux and Helicobacter pylori-associated carditis; a comparative study. Am J Surg Pathol. 2003;27:960-968.

(37.) Chen Y, Wang HH, Antonioli DA, et al. Significance of acid-mucin-positive nongoblet columnar cells in the distal esophagus and gastroesophageal junction. Hum Pathol. 1999;30:1-8.

(38.) Glickman JN, Shahsafaei A, Odze RD. The mucin core polypeptide pattern can help distinguish Barrett's esophagus (BE) from inflammation of the gastric cardia (carditis) with intestinal metaplasia. Am J Surg Pathol. 2003;27:1357-1365.

(39.) 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.

(40.) Glickman JN, Ormsby AH, Gramlich T, Goldblum JR, Odze RD. Interinstitutional variability in the interpretation of cytokeratin 7/20 staining patterns in Barrett's esophagus. Gastroenterology. 2001;120:415A.

(41.) Mohammed IA, Streutker CJ, Riddell RH. Utilization of cytokeratins 7 and 20 does not differentiate between Barrett's esophagus and gastric cardiac intestinal metaplasia. Mod Pathol. 2002;15:611-616.

(42.) El-Zimaity HMT, Graham DY. Cytokeratin subsets for distinguishing Barrett's esophagus from intestinal metaplasia in the cardia using endoscopic biopsy specimens. Am J Gastroenterol. 2001;96:1378-1382.

(43.) Hamilton SR. Pathogenesis of columnar cell-lined (Barrett's) esophagus. In: Spechler SJ, Goyal RK, eds. Barrett's Esophagus. New York, NY: Elsevier; 1985: 29-37.

(44.) Chandrasoma PT, Lokuhetty DM, DeMeester TR, et al. Definition of histopathologic changes in gastroesophageal reflux disease. Am J Surg Pathol. 2000; 24:344-351.

(45.) DeMeester SR, Wickramasinghe KS, Lord RVN, et al. Cytokeratin and DAS1 immunostaining reveal similarities among the cardiac mucosa, CIM and Barrett's esophagus. Am J Gastroenterol. 2002;97:2514-2523.

(46.) Houghton JM, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568-1571.

(47.) Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740-746.

(48.) Gillen P, Keeling P, Byrne PJ, West AB, Hennessy TP. Experimental columnar metaplasia in the canine oesophagus. Br J Surg. 1988;75:113-115.

(49.) Li H, Walsh TN, O'Dowd G, et al. Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett's esophagus. Surgery. 1994; 115:17-81.

(50.) Adler RH. The lower esophagus lined by columnar epithelium: its association with hiatal hernia, ulcer stricture, and tumor. J Thorac Cardiovasc Surg. 1963;45:13-32.

(51.) Glickman JN, Chen YY, Wang HH, et al. Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett's esophagus. Am JSurgPathol. 2001;25:569-578.

(52.) Shields H, Rosenberg SJ, Zwas FR, et al. Prospective evaluation of multilayered epithelium in Barrett's esophagus. Am J Gastroenterol. 201;96:3268 3273.

(53.) Glickman JN, Spechler SJ, Dineen T, et al. Multilayered epithelium at the squamocolumnar junction is a histological marker for gastroesophageal reflux disease. Mod Pathol. 2005;81(suppl 1):103A.

(54.) Odze RD. Diagnosis and grading of dysplasia in Barrett's oesophagus. J Clin Pathol. 2006;59:1029-1038.

(55.) Riddell RH, Goldman H, Ransohoff DE, et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional clinical information. Hum Pathol. 1983;14:931-968.

(56.) Schnell TG, Sontag SJ, Chejfec G, et al. Long-term surgical management of Barrett's esophagus with high-grade dysplasia. Gastroenterology. 2001;120: 1606-1619.

(57.) Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 200;47:251-255.

(58.) Barrett MT, Sanchez CA, Prevo LJ, et al. Evolution of neoplastic cell lineages in Barrett's oesophagus. Nat Genet. 1999;22:106-109.

(59.) Maley CC, Galipeau PC, Finley JC, et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet. 2006;38:468-473.

(60.) Maley CC, Reid BJ. Natural selection in neoplastic progression of Barrett's esophagus. Semin Cancer Biol. 2005;15:474-483.

(61.) Maley CC, Galipeau PC, Li X, et al. Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus. Can Res. 2004;64:3414-3427.

(62.) Gulizia J, Wang H, Antonioli D, et al. Proliferative characteristics of intestinalized mucosa win the distal esophagus and gastroesophageal junction (short segment Barrett's esophagus). Hum Pathol. 1999;30:412-419.

(63.) Wong DJ, Paulon TG, Prevo LJ, et al. p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. Cancer Res. 2001;61:8284-8289.

(64.) Chaves P, Crespo M, Ribeiro C, et al. Chromosomal analysis of Barrett's cells: demonstration of instability and detection of the metaplastic lineage involved. Mod Pathol. 2007;20:788-796.

(65.) Yu C, Zhang X, Huang Q, et al. High-fidelity DNA histograms in neoplastic progression in Barrett's esophagus. Lab Invest. 2007;87:466-472.

(66.) Campomenosi P, Conio M, Bogliolo M, et al. p53 is frequently mutated in Barrett's metaplasia of the intestinal type. Cancer Epidemiol Biomarkers Prev. 1996;5:559-565.

(67.) Montgomery E, Bronner MP, Goldblum JR, et al. Reproducibility of the diagnosis if dysplasia in Barrett's esophagus: a reaffirmation. Hum Pathol. 2001; 32:368-378.

(68.) 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.

(69.) Kerkhof M, van Dekken H, Steyerberg EW, et al. Grading of dysplasia in Barrett's oesophagus: substantial interobserver variation between general and gastrointestinal pathologists. Histopathology. 2007;50:920-927.

(70.) Lomo L, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: a clinical, pathologic and molecular study of a Barrett's esophagus cohort. Am J Surg Pathol. 2006;30:423-435.

(71.) Zhang X, Goyal R, Huang Q, Odze Rd. High fidelity image cytometry in neoplastic lesions in Barrett's esophagus, including basal crypt dysplasia-like atypia with surface maturation. Lab Invest. 2007;87(suppl 1):133A.

(72.) Rice TW, Zuccaro G Jr, Adelstein DJ, et al. Esophageal carcinoma: depth of tumor invasion is predictive of regional lymph node status. Ann Thorac Surg. 1998;65:787-792.

(73.) Ormsby AH, Petros RI, Henricks WH, et al. Observer variation in the diagnosis of superficial oesophageal adenocarcinoma. Gut. 2002;51:671-676.

(74.) Hong MK, Laskin WB, Herman BE, et al. Expansion of the Ki-67 proliferative compartment correlates with degree of dysplasia in Barrett's esophagus. Cancer. 1995;75:423-429.

(75.) Feith M, Stein HJ, Mueller J, et al. Malignant degeneration of Barrett's esophagus: the role of the Ki-67 proliferation fraction, expression of E-cadherin and p53. Dis Esophagus. 2004;17:322-327.

(76.) Bani-Hani K, Martin IG, Hardie LJ, et al. Prospective study of cyclin D1 overexpression in Barrett's esophagus: association with increased risk of adeno carcinoma. J Natl Cancer Inst. 200;92:1316-1321.

(77.) Ireland AP, Clark GWB, DeMeester TR. Barrett's esophagus: the significance of p53 in clinical practice. Ann Surg. 1997;225:17-30.

(78.) Ramel S, Reid BJ, Sanchez CA, et al. Evaluation of p53 protein expression in Barrett's esophagus by two-parameter flow cytometry. Gastroenterology. 1 992; 102:1220-1228.

(79.) Dorer R, Odze RD. AMACR immunostaining is useful in detecting dysplastic epithelium in Barrett's esophagus, ulcerative colitis and Crohn's disease. Am J Surg Pathol. 2006;30:871-877.

(80.) Lisovsky M, Falkowski O, Bhuiya T. Expression of alpha-methylacyl-coenzyme A racemase in dysplastic Barrett's epithelium. Hum Pathol. 2006;37: 1601-1606.

(81.) Weston AP, Sharma P, Mathur S, et al. Risk stratification of Barrett's esophagus: updated prospective multivariate analysis. Am J Gastroenterol. 2004;99: 1657-1666.

(82.) 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.

(83.) Buttar NS, Wang KK, Sebo TJ, et al. Extent of high-grade dysplasia in Barrett's esophagus correlates with risk of adenocarcinoma. Gastroenterology. 2001; 120:1630-1639.

(84.) Montgomery E, Bronner MP, Greenson JK, et al. Are ulcers a marker for invasive carcinoma in Barrett's esophagus?: data from a diagnostic variability study with clinical follow-up. Am J Gastroenterol. 2002;97:27-31.

(85.) Sampler RE. Updated guidelines for the diagnosis, surveillance, and therapy of Barrett's esophagus. Am J Gastroenterol. 2002;97:1888-1895.

(86.) Weston AP, Banerjee SK, Sharma P, Tran TM, Richards R, Cherian R. p53 protein over expression in low grade dysplasia (LGD) in Barrett's esophagus: immunohistochemical marker predictive of progression. Am JGastroenterol. 2001; 96:1355-1362.

(87.) Sharma P, Falk GW, Weston AP, et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus. Clin Gastroenterol Hepatol. 2006;4:566-572.

(88.) Conio M, Blanchi S, Lapertoso G, et al. Long-term endoscopic surveillance of patients with Barrett's esophagus: incidence of dysplasia and adenocarcinoma: a prospective study. Am J Gastroenterol. 2003;98:1931-1939.

(89.) Srivastava A, Hornick JL, Li X, et al. Extent of low-grade dysplasia is a risk factor for the development of esophageal adenocarcinoma in Barrett's esophagus. Am J Gastroenterol. 2007;102:483-493.

(90.) 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.

(91.) Montgomery E, Goldblum JR, Greenson JK, et al. Dysplasia as a predictive marker for invasive carcinoma in Barrett's esophagus: a follow-up study based on 138 cases from a diagnostic variability study. Hum Pathol. 2001;32:379-388.

(92.) Dar MS, Goldblum JR, Rice TW, et al. Can extent of high-grade dysplasia in Barrett's oesophagus predict the presence of adenocarcinoma at oesophagectomy? Gut. 2003;52:486-489.

(93.) Reid BJ, Blount PL, Rubin CE, Levine DS, Haggitt RC, Rabinovitch PS. Predictors of progression to malignancy in Barrett's esophagus: endoscopic histologic and flow cytometric follow-up of a cohort. Gastroenterology. 1992;102: 1212-1219.

(94.) Casson AG, Mukhopadhay T, Cleary KR, Ro JY, Levin B, Roth JA. p53 gene mutations in Barrett's epithelium and esophageal cancer. Cancer Res. 1991;51: 4495-4499.

(95.) Haamelin R, Flejou JF, Muzeau F, et al. TP53 mutations and p53 protein immunoreactivity in malignant and premalignant Barrett's oesophagus. Gastro enterology. 1994;107:1012-1018.

(96.) Reid BJ, Sanchez CA, Blount PL, Levine DS. Barrett's esophagus: cell cycle abnormalities in advancing stages of neoplastic progression. Gastroenterology. 1993;105:119-129.

(97.) Reid BJ, Blount PL, Rabinovitch PS. Biomarkers in Barrett's esophagus. Gastrointest Endosc Clin North Am. 2003;13:369-397.

(98.) Skacel M, Petras RE, Rybicki LA, et al. p53 Expression in low-grade dysplasia in Barrett's esophagus: correlation with interobserver agreement and disease progression. Am J Gastroenterol. 2002;97:2508-2513.

(99.) Younes M, Ertan A, Lechago LV, et al. p53 protein accumulation is a specific marker of malignant potential in Barrett's metaplasia. Dig Dis Sci. 1997;42: 697-701.

(100.) McManus DT, Olaru A, Meltzer SJ. Biomarkers of esophageal adenocarcinoma and Barrett's esophagus. Cancer Res. 2004;64:1561-1569.

(101.) Gross G, Canto M, Hixson J, et al. Management of Barrett's esophagus: a national study of practice patterns and their cost implications. Am J Gastroenterol. 1999;94:3440-3447.

(102.) Inadomi JM, Sampliner R, Lagergren J, Leiberman D, Fendrick AM, Vakil N. Screening and surveillance for Barrett's esophagus in high-risk groups: a cost utility analysis. Ann Intern Med. 2003;138:176-186.

(103.) Falk G, Ours T, Richter J. Practice patterns for surveillance of Barrett's esophagus in the United States. Gastrointest Endosc. 2000;52:197-203.

(104.) Corley DA, Levin TR, Habel LA, Weiss NS, Buffer PA. Surveillance and survival in Barrett's adenocarcinomas: a population-based study. Gastroenterology. 2002;122:633-640.

(105.) Strietz JM, Andrews CW, Ellis FH Jr. Endoscopic surveillance of Barrett's esophagus: does it help? J Thorac Cardiovasc Surg. 1993;105:383-387.

(106.) Peters JH, Clark GWB, Ireland AP, Chandrasoma P, Smyrk TC, DeMeester TR. Outcome of adenocarcinoma arising in Barrett's esophagus in endoscopically surveyed and nonsurveyed patients. J Thorac Cardiovasc Surg. 1994;108:813 822.

(107.) Spechler SJ. Dysplasia in Barrett's esophagus: limitations of current management strategies. Am J Gastroenterol. 2005;100:927-935.

(108.) Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop. Gastro enterology. 2004;127:310-330.

(109.) Eisen GM. Ablation therapy for Barrett's esophagus. Gastrointest Endosc. 2003;58:760-769.

(110.) Attwood SEA, Lewis CJ, Caplin S, Hemming K, Armstrong G. Argon beam plasma coagulation as therapy for high-grade dysplasia in Barrett's esophagus. Clin Gastroenterol Hepatol. 2003;1:258-263.

(111.) Johnston MH. Technology insight: ablative techniques for Barrett's esophagus: current and emerging trends. Nat Clin Pract Gastroenterol Hepatol. 2005; 2:323-330.

Robert D. Odze, MD, FRCP(C)

From the GI Pathology Service, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

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

Presented in part at the 47th Annual Meeting of the Houston Society of Clinical Pathologists, Houston, Tex, April 21, 2007.

Reprints: Robert D. Odze, MD, FRCP(C), Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (e-mail: rodze@partners.org).
Carditis With Intestinal Metaplasia Versus Ultrashort
Barrett Esophagus *

                                 Gastric
Feature                          Carditis   Barrett

Squamous epithelium overlying
  crypts with IM                    -          +
Hybrid glands                       -          +
Multilayered epithelium             -          +
Esophageal glands/ducts             -          +
Crypt disarray                     +/-        ++
Crypt atrophy                      +/-        ++
Incomplete IM k complete IM        +/-        ++

* Modified with permission from Am J Surg Pathol.35
Copyright 2007, Lippincott Williams & Wilkins. IM
indicates intestinal metaplasia; -, not present; +,
present in less than 50% of cases; +/-, may or may
not be present; and ++, present in more than 50% of
cases.
Gale Copyright: Copyright 2008 Gale, Cengage Learning. All rights reserved.