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
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
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
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
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
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
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
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