Rodger C. Haggitt Slide Seminar: Lesions of Esophagus, Stomach, and Duodenum
Moderators: Dr. Cecilia Fenoglio-Preiser and Dr. Wendy Frankel
Case 3 -
Barrett's Esophagus: Dysplasia and Carcinoma
Robert E. Petras, M.D., FASCP, FACG
Associate Professor of Pathology
Northeastern Ohio Universities, College of Medicine
National Director for Gastrointestinal Pathology Services, AmeriPath, Inc.
67 year-old woman with Barrett's esophagus. R/O dysplasia.
Description of Slide and Discussion
The number of mitoses figures are more than is usually encountered in Barrett's esophagus, even those
examples of Barrett's esophagus with ulceration, active inflammation and marked regeneration. Many of
the mitoses figures are arrested in metaphase characterized by the "ring" morphology. These are
characteristic changes associated with colchicine . Upon questioning the gastroenterologist, this
patient was receiving colchicine as therapy for primary biliary cirrhosis. In addition to the effects on
mitoses, colchicine has been associated with increased apoptosis, epithelial stratification, and loss of
polarity that can mimic epithelial dysplasia
changes present in this biopsy specimen.
Case 3 - Slide 1
Diagnosis: Specialized columnar epithelium (intestinal metaplasia) consistent with Barrett's esophagus showing
cytopathologic effects of colchicine mimicking low-grade epithelial dysplasia.
Barrett's esophagus, the eponym given to columnar epithelium-lined esophagus, is acquired through
chronic gastroesophageal reflux
Traditionally, it was defined as the presence of columnar
epithelium lining the tubular esophagus above the level of the LES . For purposes of cancer
surveillance, the American
College of Gastroenterology (ACG) now defines Barrett's esophagus as an endoscopic change in esophageal
epithelium of any length that contains intestinal metaplasia
Barrett's esophagus would be little more than a medical curiosity if not for its complications:
ulcer, stricture, bleeding, and carcinoma. It is the association with carcinoma that has brought
gastroesophageal reflux disease and Barrett's esophagus to so much attention . Although the exact
magnitude of the cancer risk is unknown, the high prevalence and dismal outcome of carcinoma complicating
have caused the ACG to recommend that patients with longstanding reflux
symptoms have endoscopic examination to detect Barrett's esophagus . Once Barrett's esophagus is
discovered, such patients should undergo endoscopic surveillance.
DIAGNOSIS OF BARRETT'S ESOPHAGUS
The Clinical Diagnosis of Barrett's Esophagus
Endoscopy remains the mainstay for diagnosing Barrett's esophagus . In general, the color
(orange-red) and appearance (velvety) of Barrett's esophagus as seen through the endoscope is similar to
that of gastric mucosa. Barrett's esophagus can be circumferential or tongue-like extensions of
orange-red mucosa into the tubular esophagus . Occasionally, Barrett's esophagus can present as an
island of orange-red mucosa entirely surrounded by the more pale pink to gray-white squamous epithelium
of the esophagus. Some endoscopists augment endoscopic visualization with the use of vital stains such
as methylene blue
Since other conditions such as a hiatal hernia, especially one occurring in
the setting of severe gastroesophageal reflux, can sometimes mimic Barrett's esophagus endoscopically,
the endoscopist's impression of Barrett's esophagus must be confirmed histologically
The Histologic Diagnosis of Barrett's Esophagus
Three epithelial types were described in traditionally defined Barrett's esophagus and include
junctional epithelium (gastric cardia-like), gastric fundic-type epithelium, and specialized columnar
epithelium (incomplete intestinal metaplasia)
. The junctional epithelium is composed of glands and
pits that resemble the gastric cardia except for some atrophy and inflammation. The glands are composed
of mucus-secreting cells
Chief, parietal, Paneth's, enterochromaffin, and goblet cells are not
encountered in junctional epithelium. Gastric fundic-type epithelium, encountered in some cases of
traditionally-defined Barrett's esophagus, is virtually identical to that of the normal gastric body
except that, again, there is usually some degree of inflammation and atrophy. Specialized columnar
epithelium (incomplete intestinal metaplasia) is a distinctive epithelial type that is virtually unique
to and considered diagnostic for Barrett's esophagus. Furthermore, this epithelial type (intestinal
metaplasia) defines the cancer surveillance group (See below)
Specialized columnar epithelium histologically can occur in a flat or villous configuration and
consists of goblet cells and columnar cells. The goblet cells contain mucin that stains positively both
with periodic acid-Schiff and with Alcian blue at pH 2.5. These mucins are most often a combination of
sialomucins and sulfated mucins
The columnar cells between goblet cells most often resemble
gastric foveolar epithelium or rarely intestinal absorptive cells. The cells lack absorptive capability
or ultrastructural features of true intestinal absorptive cells and, therefore, the term "incomplete
intestinal metaplasia" has been applied . Specialized columnar epithelium can also contain Paneth's
cells and enterochromaffin cells
and can occasionally overlie simple mucus-type glands, or even
gastric body-like glands.
The principal differential diagnostic consideration is a gastric heterotopia. Endoscopists encounter
patches of ectopic gastric tissue, appearing as orange-red islands of abnormal mucosa surrounded by
normal pink to white squamous esophageal mucosa in approximately 4% to 10% of patients who undergo upper
endoscopy . These foci of gastric tissue occur in the cervical esophagus, are often referred to as
inlet patches, and are thought to represent embryonic rests. Histologically, they can be similar to
Barrett's esophagus and they are distinguished from Barrett's clinically by their cervical location,
their separation from the stomach by intact esophageal squamous mucosa, and lack of association with
Problems with the Histological Diagnosis of Barrett's Esophagus
Intestinal metaplasia of the stomach can be histologically indistinguishable from specialized
columnar epithelium of Barrett's esophagus . So-called "short-segment" Barrett's esophagus
(intestinal metaplasia in the distal esophagus measuring <3 cm) can be difficult to distinguished from
intestinal metaplasia of the cardia at or near a normally placed esophagogastric junction . The ACG
suggests that this distinction be made at endoscopy
That said, although intestinal metaplasia at
a normally placed esophagogastric junction may not technically be Barrett's esophagus (because it is not
in the anatomic esophagus), it is possible that this epithelial type at that location increases the risk
of developing adenocarcinoma of the gastric cardia or gastroesophageal junction
several lines of reasoning that associate intestinal metaplasia at the gastroesophageal junction with
carcinoma of the gastroesophageal junction, lower esophagus and gastric cardia including: a) the
prevalence of intestinal metaplasia at the gastroesophageal junction is proportional to the length of
specialized columnar epithelium in Barrett's esophagus
b) carcinomas of the cardia and Barrett's
associated carcinoma share common morphology, epidemiology, risk factors, frequency of gastroesophageal
reflux and prognosis (see below), c) carcinoma of the cardia and Barrett's-associated carcinoma have
shown a similar increased incidence
A proposed classification and clinical approach is
outlined in Table 1.
Table 1: Classification and Clinical Approach for Columnar Cells in the Esophagus or Intestinal Metplasia at the Gastroesophageal Junction
|Classification ||Association with GERD** ||Association with Carcinoma ||Endoscopic Surveillance|
|Barrett's esophagus with specialized columnar epithelium ||Variable/Yes ||Yes ||Yes|
|Columnar epithelium of esophagus without specialized columnar epithelium ||Yes ||Unlikely ||Probably Not|
|Intestinal metaplasia at gastroesophageal junction ||Unclear ||Probable ||Unclear|
*Modified from Reference 19.
**GERD = gastroesophageal reflux disease.
Reiterating, Barrett's esophagus is now defined as a change of esophageal epithelium of any length,
recognize at endoscopy that is proved by biopsy to contain intestinal metaplasia
practice is to confirm intestinal metaplasia by using an Alcian blue/PAS combination stain with a
hemotoxylin counterstain. The updated ACG practive guidelines encourage use of at least an Alcian blue
stain citing that its use decreases the change of missing goblet cells or of misinterpreting cells with
prominent cytoplasmic vacuoles as goblet cells .
If one uses a routine Alcian blue/PAS stain in this setting, one must be aware of the potential
Alcian blue positive staining pitfalls that are not considered to be specialized columnar epithelium of
Barrett's esophagus. These include the submucosal glands of the esophagus and their secretions, positive
staining in gastric type glands or pancreatic acinar metaplasia, the regenerative zone of gastric type
epithelium, the multilayered epithelium and the so-called columnar blues. It is postulated that
multilayered epithelium and columnar blues may be precursor cells of specialized columnar epithelium but
without goblet cell morphology, the alcian blue positive staining of the multilayered epithelium and
columnar blues is not considered Barrett's esophagus.
CARCINOMA AND CANCER SURVEILLANCE IN BARRETT'S ESOPHAGUS
Cancer Risk and Surveillance
Patients with Barrett's esophagus are at increased risk for esophageal adenocarcinoma
exact magnitude of the risk is unknown and some suggest that the risk could be overestimated because of
publication bias . Most prevalence rates for carcinoma complicating Barrett's esophagus come from
referral institutions and range from 10%-15%
Cancer prevalence represents patients in a
population already with carcinoma. The true problem in assessing the need for cancer surveillance
involves patients with Barrett's esophagus who do not yet have carcinoma. What is their risk of
developing carcinoma (incidence) and does that risk justify the cost of a cancer surveillance program?
In prospective studies, Robertson et al reported an incidence of 1786 cases of Barrett's associated
carcinoma per 100,000 population per year  and Hameeteman et al reported 1920 cases per 100,000 per
year , rates that are 350 times and 125 times the rate of esophageal carcinoma in the general
Though most agree that Barrett's esophagus places patients at risk for esophageal adenocarcinoma, no
consensus has emerged as to whether the increased risk justifies the cost of a cancer surveillance
program. Van der Veen et al concluded that systematic endoscopic surveillance was not indicated in
patients with Barrett's epithelium, citing that there was no difference in survival between patients with
Barrett's esophagus and a control population . In a subsequent study of the same cohort with eight
additional years of follow-up, eight additional patients had developed esophageal adenocarcinoma .
This represented 1 carcinoma per 180 patient years or a forty-fold increased risk. Despite this fact and
the 50% greater death rate in the Barrett's esophagus group vs. controls, the authors concluded that too
few patients actually died of Barrett's esophagus-associated carcinoma (only two deaths), and therefore,
formal surveillance would have been of little benefit.
Though controversial, in the absence of a definitive study to the contrary, it is prudent to place
all patients with Barrett's esophagus into a cancer surveillance program. The American
College of Gastroenterology recommends cancer surveillance for Barrett's esophagus with the surveillance
goal being prevention of carcinoma or the detection of carcinoma in an early and potentially curable
phase . The marker used as the end point for cancer surveillance programs is identification of
epithelial dysplasia in a biopsy specimen.
Dysplasia, the presumed precancerous epithelial lesion, has been regularly recognized in esophageal
specimens adjacent to and distant from Barrett's-associated adenocarcinomas
evidence suggests that dysplasia may not only be a marker for carcinoma, but may itself be the early
carcinomatous change that can progress to invasive carcinoma . Although the circumstantial evidence
for the dysplasia-carcinoma sequence is compelling, the progression of dysplasia to carcinoma is still
largely unproven and the time course unknown. The potential benefits (largely unknown) of removing a
dysplastic esophagus must be weighed against the relatively high mortality associated with esophagectomy
(estimated to be 5-15%) and the dismal outcome in patients who present with invasive adenocarcinoma of
the esophagus (34% survival at two years and 14.5% survival at five years)
Dysplasia in Barrett's Esophagus: Histopathologic Diagnosis, Significance, and Proposed Patient Management
Dysplasia is recognized histologically and criteria for identifying these changes in ulcerative
colitis are applied in studying Barrett's epithelium
A reaffirmation of criteria with numerous
illustrations has been published . The term dysplasia in Barrett's esophagus should only be used to
describe a change that is unequivocally neoplastic. As with inflammatory bowel disease, dysplasia in
Barrett's epithelium can be closely mimicked by reparative epithelial changes associated with active
inflammation and ulcer.
Dysplasia and repair are associated with nuclear enlargement and hyperchromasia, increased mitotic
figures, and decreased intracellular mucin. However, some histologic features favor repair over
dysplasia. The nuclei of repair are often round to oval with smooth external contours, are evenly
spaced, do not overlap, contain granular chromatin with single or multiple chromocenters/nucleoli, and
are remarkably similar to one another in both size and appearance. In contrast to dysplasia, the nuclear
to cytoplasmic size ratio of reparative cells is often decreased, especially in cells adjacent to
ulcerated areas. Nearby active inflammation helps to confirm a diagnosis of repair. Features that favor
dysplasia over repair are: a) variable nuclear hyperchromasia associated with pleomorphism, b) irregular
nuclear contours, c) marked nuclear stratification with crowding and overlap, d) loss of nuclear
polarity, e) nuclear and architectural abnormalities that are visible at low
magnification , and
involvement of the surface epithelium. Some Barrett's-associated dysplasias can look similar to colonic
or small intestinal adenomas
however, in my experience the majority do not.
Dysplasia has been reported to occur in all three types of epithelia seen in traditionally defined
Barrett's esohpagus. However, it is certainly more frequent in areas of specialized columnar epithelium
 and it is unlikely that cancer ever occurs except in patients with specialized columnar epithelium
It is frequently difficult or impossible to ascertain epithelial types in mucosa totally
replaced by dysplasia or carcinoma .
Reiterating, most use a modification of the Inflammatory Bowel Disease-Dysplasia Morphology Study
Group Classification in Barrett's epithelium
Under this three-tiered system, biopsy findings are
classified as negative for dysplasia, positive for dysplasia, or indefinite for dysplasia. Biopsy
specimens interpreted as positive for dysplasia are further subdivided as low-grade or high-grade
dysplasia based upon the degree of cytologic change present. In low-grade glandular dysplasia, the
abnormal nuclei are limited to the basal half of the cells. In high-grade glandular dysplasia, more
severe cytologic and architectural alterations are present. Hyperchromasia and pleomorphism are more
marked. Nuclear crowding and stratification are often present. Nuclei may be found in the luminal half
of the cells. No distinction is made between high-grade dysplasia and carcinoma in situ in this
system. If equivocal changes are present, they are usually due to epithelial repair associated with
active inflammation. In this setting the specimen is best classified as indefinite for dysplasia. In my
opinion, high-grade glandular dysplasia can be reliably detected by an experienced surgical pathologist,
but because of the marked interobserver variation reported in diagnosing low grade glandular dysplasia
and indefinite for dysplasia
and similar outcome
I follow the guidelines of Reid et al
 and have adopted similar management for either diagnosis.
The histologic grade of dysplasia has clinical significance
Infiltrating carcinoma is a
rare event in patients with Barrett's esophagus initially negative for dysplasia (0-3%). In contrast,
60% of patients with initial high-grade dysplasia have developed or already have infiltrating carcinoma
The results are intermediate for low-grade dysplasia and indefinite for dysplasia (10-28%
One study stands out in stark contrast by observing a much lower cancer incidence
rate in high-grade dysplasia (16%)
. This study has been criticized for its possible "overreads"
because 70% of their patients had at least low-grade dysplasia, in contrast to most other studies in
which the the prevalance of low-grade dysplasia is only about 5% .
During surveillance endoscopy, four quadrant biopsy specimens at 1-2 cm increments are obtained
throughout the entire length of the Barrett's epithelium
Patients negative for dysplasia
can safely continue regular surveillance (q 1-2 years). The ACG suggests that after 2 negative
surveillance endoscopies, that the interval can be increased to 3 years . Investigators recommend
shorter term follow-up for "indefinite" and "low-grade" dysplasia. The ACG now suggests 1 year 
although I prefer their former recommendation of 6 months . Management of high-grade dysplasia
remains controversial. Some recommend continued surveillance for some patients
majority recommend esophagectomy for the surgically fit candidate if life expectancy exceeds 10 years
. Since the operative mortality and morbidity of esophagectomy is high, it is prudent to confirm a
diagnosis of high-grade dysplasia before moving on to esophagectomy. Immediate re-endoscopy with
should be performed. This re-biopsy approach has the advantage that
intramucosal or invasive carcinoma may be detected with careful endoscopic re-examination and extensive
re-biopsy, thus making the decision for esophagectomy easier. The ACG recommends that HGD be confirmed
by an "expert" pathologist . If after an original diagnosis of high grade dysplasia the follow-up
endoscopy with biopsy is negative, then the original specimens should be re-reviewed. If high grade
dysplasia is again confirmed, some form of intervention is recommended .
Investigators at the Mayo Clinic reported that focal high-grade dysplasia (single focus of <5
crypts) progressed at a relatively low rate (14%) vs. their more diffuse high-grade dysplasia cases (56%)
. Based on this, the ACG recommended that patients with focal high-grade dysplasia be followed with
intensive endoscopic surveillance (e.g., q 3 months)
. Other studies found no difference in outcome
between focal and diffuse high-grade dysplasia suggesting that this differential management approach
should be abandoned . My approach to patient management is summarized in Table 2.
Table 2: Dysplasia in Barrett's Epithelium: Management Plan Based Upon Histologic Interpretation*
|Histologic Interpretation ||Management|
|Negative ||Yearly or every other year surveillance; after2 negative endoscopies, interval can be increased to 2-3 years|
|Indefinite for dysplasia or ||Medical therapy for reflux, repeat biopsy in positive: low-grade dysplasia 6 months - if negative x 2 go to yearly surveillance and recommendations similar to negative (see above)|
|If indefinite/low-grade dysplasia persists, ||continue q 6 month surveillance until dysplasia progresses or regresses|
|Positive: high-grade dysplasia ||Immediate re-endoscopy with biopsy/confirm (see text) then consider esophagectomy or other intervention|
*Modified from other proposed management plans, see references
Investigators at the University of Washington favor intense endoscopic surveillance for high-grade
dysplasia and recommend esophagectomy only when intramucosal adenocarcinoma has been detected . The
operative mortality for esophagectomy in their series was high. Although the results of their
surveillance are considered acceptable, the biopsy protocol is so demanding and expensive that many
believe that it can not be applied outside of a research setting. Furthermore, advanced cancers with
metastasis have developed in 5% of patients followed by surveillance only for high-grade
Interobserver variation in histologic diagnosis (high-grade dysplasia versus intramucosal carcinoma) may
limit their approach .
Dysplasia is relatively rare in patients with Barrett's esophagus but data suggest that when biopsy
specimens are positive for high-grade dysplasia, there is considerable risk that infiltrating carcinoma
is already present. We reported our experience with esophagectomy for high grade dysplasia without
endoscopic abnormality. We discovered a 40% prevalence of intramucosal adenocarcinoma in the resection
This proportion has been consistent in the surgical literature . This fact along
with the relatively low mortality rate for esophagectomy in places with experience allow us to recommend
esophagectomy for high grade dysplasia in patients physically sound enough to survive such an operation
Others have made similar recommendations .
While it is tempting to conclude that patients with early carcinoma detected by surveillance
endoscopy have benefited from early resection, initial enthusiasm at these apparent successes must be
tempered by the realization that in at least one series the operative-related death rate was 25% .
In addition, one must critically consider the patients who underwent surgery for high-grade dysplasia in
whom only high-grade dysplasia was identified in the resection specimens. There is currently no
conclusive evidence that they would have ever developed invasive carcinoma and if they did, the time
course from dysplasia to carcinoma is unknown. Prelimnary data suggest that there is a more favorable
survival in patients participating in surveillance endoscopy programs than in those patients who are not
Other options for treatment of dysplasia and early cancer in Barrett's esophagus are usually reserved
for high surgical risk patients and include photodynamic therapy, endoscopic ablation, and endoscopic
Restoration of squamous mucosa after laser (or other) ablation of Barrett's epithelium in an
achlorhydic environment has been described
This type of treatment for Barrett's esophagus could
obviate the need for surveillance by eliminating the cancer risk. However, long term follow up studies
are required to detect any effect on the incidence of carcinoma. Furthermore, lifelong therapy with
proton pump inhibitors may be required to prevent regrowth of Barrett's epithelium. The long-term
side-effects of this drug in humans are unknown but appear to be minimal. Another potential problem is
that partially ablated mucosa can heal with squamous epithelium overlying buried specialized columnar
epithelium. There are reports of carcinoma developing from these buried metaplastic tissues .
Dysplasia in Barrett's Esophagus: The Role of Other Pathological Techniques
Mucin histochemistry has been extensively investigated in Barrett's esophagus and dysplasia
Some retrospective analyses have shown an association between adenocarcinoma and the
presence of sulfated acid mucins in the non-goblet cells of the specialized columnar epithelium .
However, others have concluded that the presence of sulfated mucins in these cells is so common that it
is of no predictive value as a marker for dysplasia or carcinoma
Heightened cancer risk has
also been described with loss of o-acetylated mucin, aberrant expression of blood group antigens, and
abnormalities of sucrase - isomaltose, but these are not used clinically
Reid et al have reported their experience with deoxyribonucleic acid (DNA) analysis by flow cytometry
in patients with Barrett's esophagus
In these studies, carcinoma and dysplasia in biopsy
specimens were highly correlated DNA cell cycle abnormalities. Furthermore, there appeared to be
progression of DNA abnormalities with increasing epithelial dysplasia. Investigators from this same
institution have also demonstrated a strong association between multiple different DNA aneuploid cell
populations and adenocarcinoma in Barrett's esophagus. Others, however,  have demonstrated
discordance between DNA aneuploidy, dysplasia, and carcinoma. It is possible that flow cytometry could
be a useful adjunct to standard histologic assessment in cancer surveillance of patients with Barrett's
esophagus, but more study is needed. Since some examples of Barrett's associated adenocarcinoma and
dysplasia lack DNA abnormalities by flow cytometry
it is clear that this technique could not be
used alone in a cancer surveillance program. The role of DNA analysis could be in the identification of
a subgroup of Barrett's patients requiring less frequent surveillance . Few, if any, patients with
histology negative for dysplasia and normal DNA content have progressed to adenocarcinoma . In these
patients, one could argue that surveillance intervals could be extended to up to 5 years. At the moment,
DNA content analysis must be considered a research tool and is rarely used clinically.
Chromosomal imbalances by comparative genomic hybridization  and abnormalities of various genes
have been described in Barrett's associated adenocarcinoma including p53, APC, DCC, and Rb
is one of the more commonly studied gene loci because abnormalities of p53 gene usually produce an
altered protein that can be studied using immunocytochemistry. Abnormal p53 protein has been found in
few or no specimens classified as negative for dysplasia. In contrast, abnormal p53 expression has been
identified in many low-grade dysplasia cases and in approximately two thirds of the high grade dysplasias
and carcinomas examined. Although aberrant p53 expression may be an objective marker for neoplastic
progression, it cannot be used alone in a surveillance program and the current clinical utility is
unknown. That said, p53 and Ki67 staining can be used to help diagnose low-grade dysplasia
Similarly, abnormal expression of C-erbB2, H-ras, C-myc, TGF , EGF, EGFr, have been reported, but are not
used in clinical management .
Brush cytology can help in the diagnosis and management of patients with Barrett's epithelium by
recognizing specialized columnar epithelium or carcinoma
Since brush cytology is done via the
endoscope, biopsy is performed as well and cytology plays only a complimentary role. Non-endoscopically
directed balloon cytology for cancer surveillance in Barrett's esophagus has been described . The
feasibility of doing molecular studies on fluid-based cytologic preparations has been proved and could
also be an adjunct in surveillance
The ACG states that dysplasia is the best current indication of the risk of cancer in Barrett's
esophagus. The ACG also concludes that a marker other than dysplasia in identifying a high risk group
on which to perform surveillance has not yet been established .
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