Hepatocyte Paraffin 1 Antigen as a Biomarker for Early Diagnosis of Barrett Esophagus
Am J Clin Pathol
Hepatocyte Paraffin 1 Antigen as a Biomarker for Early Diagnosis of Barrett Esophagus
Jennifer A. Jeung
Justin J. Coran
Diana M. Cardona
Upon completion of this activity you will be able to: • define the American College of Gastroenterology (ACG) requirements for a diagnosis of Barrett esophagus and compare and contrast these with the British Society of Gastroenterology (BSG) requirements. • define the antigen target of hepatocyte paraffin 1 (HepPar1) antibody and describe the pattern of immunohistochemical staining. • discuss the different morphologic features that can be identified in distal esophageal biopsies and how these correlate with clinical impression and potential markers of intestinal differentiation.
Barrett esophagus; Carbamoyl phosphate synthetase I; Hepatocyte paraffin 1; HepPar1
A b s t r a c t
We evaluated hepatocyte paraffin 1 (HepPar1)
antigen expression, a sensitive marker of small
intestinal differentiation, in combination with
morphologic features to demonstrate intestinal
differentiation in cases equivocal for Barrett esophagus
(BE). Clinicopathologic features and HepPar1
expression were recorded for 54 BE cases, 45
consistent with reflux esophagitis (RE) cases, and 65
“suspicious” for BE (SBE) cases. The SBE category
included RE cases with 2 or more morphologic changes
associated with BE or metaplastic reaction to injury
(eg, multilayered epithelium, squamous islands, goblet
cell mimickers, pancreatic metaplasia). HepPar1 was
expressed in all 54 BE cases, 4 of 45 RE cases, and 24
of 65 SBE cases. In SBE cases, 2 or more morphologic
changes were associated with HepPar1 expression
in 37% of cases (24/65), 3 or more features in 59%
(13/22), and 4 or more features in 100% (4/4) (P ≤
.004). The combination of certain morphologic changes
and HepPar1 expression in clinically suspicious distal
esophageal biopsy cases without goblet cells supports
the presence of evolving intestinal metaplasia.
Barrett esophagus (BE), which develops secondary to
chronic gastroesophageal reflux disease, is the major risk
factor for the development of esophageal dysplasia and
adenocarcinoma.1-7 Studies suggest that the histologic changes
seen in BE are a continuum from an initial metaplastic
change of the squamous esophageal mucosa to an
intermediate columnar epithelium followed by goblet cell
metaplasia.2,8,9 This columnar epithelium with goblet cells, defined
as “intestinal metaplasia” (IM), is widely accepted as having
potential for malignant progression.5,7 The American
College of Gastroenterology requires an endoscopically
identifiable columnar-type mucosal change in the distal esophagus
combined with histologic confirmation of goblet cells for
the diagnosis of BE.7 The American Gastroenterological
Association additionally supports the requirement of goblet
cells on biopsy after endoscopic identification of
metaplastic columnar epithelium replacing the normal stratified
squamous epithelium of the distal esophagus on endoscopy,
stating that “intestinal metaplasia is the only type of
esophageal columnar epithelium that predisposes to malignancy.”10
However, other studies have suggested that goblet cells
alone may not be the earliest histologic indicator of
intestinal differentiation.2,11 This metaplastic columnar epithelium
of the esophagus without goblet cells demonstrates DNA
content abnormalities similar to columnar epithelium with
goblet cells,12 and immunohistochemical reactivity against
Cdx-2, villin, and Das-1 highlights the presence of intestinal
differentiation.11,13-15 In fact, this non–goblet cell
metaplastic columnar epithelium may have a similar or possibly
greater risk of neoplastic progression than that of columnar
epithelium with goblet cells.2,3,12,16,17
Hepatocyte paraffin 1 (HepPar1) antigen, recently
identified as carbamoyl phosphate synthetase I (CPS1), the
ratelimiting enzyme in the urea cycle,18 is a marker of intestinal
differentiation. Specifically in small intestinal mucosa,
antibody to HepPar1 antigen demonstrates granular cytoplasmic
reactivity within absorptive cells without reactivity in goblet
or Paneth cells. Several studies have identified HepPar1
antibody as a sensitive and specific marker of the IM found
in BE.1,19 An advantage of assessing CPS1 expression at the
gastroesophageal junction (GEJ) is its presence in the
absorptive cells of IM but absence within the columnar cells of
Although in the United States the presence of goblet cells
in distal esophageal biopsy specimens is necessary for a
diagnosis of BE, several other morphologic characteristics have
been shown to be highly associated with BE. For example,
Shields et al20 identified multilayered epithelium and basal
squamous-appearing cells with superficial columnar cells as
a transitional state in squamous-to-columnar metaplasia that
may be nearly 100% specific for cases of distal esophageal
IM.9,14,21 Srivastava et al22 described crypt atrophy,
branching, and disarray, in addition to multilayered epithelium, as
also being specific for BE. In addition, goblet cell mimickers,
such as “pseudogoblet cells” and “columnar blues,”
pancreatic metaplasia, Paneth cells, and reepithelialized squamous
mucosa are also thought to represent metaplastic change
within the distal esophagus.11,23-26
As the incidence of esophageal adenocarcinoma
continues to increase,27 identifying BE through endoscopic
screening with biopsies remains increasingly important.7,28,29
Defining the earliest changes associated with intestinal
differentiation and identifying at-risk patients is crucial for
care given the survival advantage of early cancer detection
vs symptomatic presentation.7 By using HepPar1 antigen
expression as a sensitive and specific marker of intestinal
differentiation, our purpose in this study was to assess the
presence of BE-associated features as a way to predict the
presence of IM within distal esophageal biopsy specimens
without goblet cells. In clinically suspected cases, the
presence of these BE-associated morphologic features and
expression of HepPar1 antigen may indicate the need for
increased surveillance or a shorter interval to repeated biopsy
in an attempt to diagnose BE according to the current
American College of Gastroenterology guidelines.
Materials and Methods
Case Selection and Morphologic Analysis
This study was approved by the institutional review
board at the University of Florida College of Medicine,
Gainesville. Any case representing a patient younger than 18
years was excluded from this study per institutional review
board permission requirements.
By using the diagnostic term “consistent with reflux
esophagitis” (RE), we retrospectively searched the
Department of Pathology files for cases that had a final diagnosis
of RE between January 1, 2000, and April 1, 2009, and
initial case selection consisted of 587 total cases. All available
clinical records were reviewed to determine the sex and age of
patients, endoscopic appearance of the distal esophagus/GEJ
region, the presence or absence of a previous diagnosis of BE
or IM, and available clinical follow-up. In addition, cases with
the final diagnosis of “Barrett esophagus” were searched from
January 1, 2006, to December 31, 2006, and the first 100 cases
Based on the procedure reports, endoscopic findings
were recorded as positive or negative for features suggestive
of or consistent with BE, including presence of an
irregular Z-line, “salmon-colored mucosa,” and/or displacement
of the squamocolumnar junction proximal to the GEJ. Per
endoscopic reports, distal esophageal biopsy specimens were
obtained from the neosquamocolumnar junction in cases
with endoscopic abnormalities or the actual squamocolumnar
junction/GEJ in endoscopically normal-appearing cases. In
addition, distal esophageal biopsy specimens obtained from
patients older than 18 years with reportedly normal
endoscopic findings and no significant histologic changes were
used as control samples.
Category selection was determined after the cases were
reviewed at a multiheaded scope by 2 pathologists (J.A.J.
and D.M.C.), and inclusion required histologic identification
of both squamous and glandular mucosa (squamocolumnar
mucosa) for each case. Cases originally diagnosed as
consistent with RE (defined by the presence of intraepithelial
eosinophils associated with basal cell hyperplasia and elongation
of the lamina propria rete pegs in the squamous component)
were reviewed, and the columnar component was assessed for
the presence of “BE-associated” histologic features. The cases
that had 2 or more BE-associated morphologic features in the
columnar component—crypt disarray and atrophy,
multilayered epithelium, Paneth cells, squamous mucosal islands,
pancreatic metaplasia, or columnar cells with basophilic mucin on
H&E stain—were categorized as “suspicious” for BE (SBE).
A total of 65 cases met these criteria and were included in the
SBE category. Of the remaining cases, in which the features
consistent with RE were confirmed and fewer than 2
BEassociated features were identified, the first 45 cases were kept
for inclusion in the study.
Cases involving patients who had a previous diagnosis
of BE were excluded from the RE and SBE categories. For
the BE cases, the diagnosis was confirmed by the
reviewing pathologists, and the first 54 cases were included in
the study. The presence of any BE-associated morphologic
© American Society for Clinical Pathology
feature and/or additional features associated with IM
(incomantibody, antihuman HepPar1 (clone OCH1E5, DAKO North
plete IM, epithelium with gastric foveolar mucosa intermixed
America, Carpinteria, CA) at a 1:50 dilution, was applied
with goblet cells; complete IM, epithelium with goblet cells
to the sections at 37°C for 32 minutes. Presence of the
and absorptive enterocytes with a brush border; squamous
antigen was visualized using the UltraView DAB detection
epithelium overlying columnar crypts with IM; and hybrid
kit (Ventana Medical Systems). Slides were counterstained
glands) were recorded for those cases. In addition, the
preswith Ventana Hematoxylin, taken off the stainer, and then
ence of low-grade dysplasia, high-grade dysplasia, and/
dehydrated, cleared, and mounted with permanent mounting
or esophageal adenocarcinoma as previously diagnosed by
media. Immunoreactivity was considered positive if cells
consensus among gastrointestinal pathologists was recorded.
demonstrated discrete granular cytoplasmic staining.
Immunohistochemical staining was performed by routine
The presence of HepPar1 antibody immunoreactivity was
methods on 4-μm-thick, formalin-fixed, paraffin-embedded
correlated with the recorded morphologic findings in RE, BE,
tissue sections. Briefly, after the slides were dried for 2 hours
in a 60°C oven, they were placed on a Ventana BenchMark
automated immunostainer (Ventana Medical Systems,
Tucson, AZ) and dewaxed, and heat-induced epitope retrieval
was performed with the Ventana CC1 retrieval solution for
and SBE cases and clinical features using χ2 analysis.
The clinical features of the patient groups are
summa30 minutes at 95°C to 100°C. Primary mouse monoclonal
rized in ❚Table 1❚. ❚Table 2❚ summarizes the morphologic
Clinical and Endoscopic Features of Patient Groups
Age, mean (range) y
Endoscopy findings suspicious for Barrett esophagus†
* Data are given as number (percentage) unless otherwise indicated.
† Suspicious findings included a proximally displaced squamocolumnar junction, an irregular Z line, and salmon-colored mucosa.
Differential Expression of HepPar1 Antigen in Distal Esophageal Biopsy Specimens*
(n = 45)
“Suspicious” for Barrett
Esophagus (n = 65)
(n = 54)
findings and HepPar1 immunohistochemical results for all
cases. Within the RE category, 19 cases demonstrated 1
BEassociated morphologic feature (multilayered epithelium,
squamous mucosal islands, pancreatic metaplasia, or
nongoblet columnar cells with basophilic mucin). Only 4 (9%) of 45
cases demonstrated focal HepPar1 antibody immunoreactivity
❚Image 1A❚ and ❚Image 1B❚; 2 of the 4 had 1 of the
aforementioned BE-associated morphologic features and endoscopic
features suspicious for BE. The 54 BE cases demonstrated
the following morphologic features: 46 (85%) had incomplete
IM; 8 (15%), complete IM; 27 (50%), squamous epithelium
overlying crypts with IM; 7 (13%), hybrid glands; 19 (35%),
crypt disarray and atrophy; 9 (17%), multilayered epithelium;
13 (24%), Paneth cells; 24 (44%), squamous mucosal islands;
and 3 (6%), pancreatic metaplasia. In addition, 7 of the 54 BE
cases contained low-grade dysplasia, 3 had high-grade
dysplasia, and 1 had esophageal adenocarcinoma. HepPar1 antigen
was expressed in all 54 of the BE cases (100%) ❚Image 1C❚
and ❚Image ID❚. The expression of HepPar1 antigen was lost in
areas of low-grade dysplasia, high-grade dysplasia, and
esophageal adenocarcinoma ❚Image 2❚. None of the 5 control cases
demonstrated HepPar1 antigen expression (data not shown).
❚Image 1❚ A, Distal esophageal mucosa with evidence of reflux esophagitis demonstrated by basal cell hyperplasia and
intraepithelial eosinophils (H&E, ×200). B, Immunohistochemical stain using hepatocyte paraffin 1 (HepPar1) antibody
demonstrates no expression in biopsy consistent with reflux esophagitis (×200). C, Distal esophageal biopsy demonstrating
columnar mucosa with goblet cells (intestinal metaplasia [IM]) histologically diagnostic for Barrett esophagus (H&E, ×200).
D, HepPar1 antigen expression is identified in areas of IM (×200).
© American Society for Clinical Pathology
The SBE group (n = 65) demonstrated the following
BE-associated morphologic features: 54 (83%) had nongoblet
columnar cells with basophilic mucin, 39 (60%) had
multilayered epithelium, 26 (40%) had pancreatic metaplasia, 31
(48%) had squamous mucosal islands, 3 (5%) had Paneth
cells, and 3 (5%) had crypt disarray and atrophy. HepPar1
antigen was expressed in 24 (37%) of 65 cases ❚Image 3❚,
with 4 additional cases demonstrating focal expression.
HepPar1 antigen expression was identified as discrete granular
cytoplasmic immunoreactivity in the vicinity of the described
BE-associated features, most commonly within columnar
cells adjacent to or within pancreatic metaplasia, multilayered
epithelium, or columnar cells with blue mucin. The presence
of 2 or more BE-associated features was associated with
HepPar1 antigen expression in 24 (37%) of 65 cases, 3 or more
features with CPS1 expression in 13 (59%) of 22 cases, and 4
or more features with CPS1 expression in 4 (100%) of 4 cases
(P ≤ .004). Specifically, multilayered epithelium, pancreatic
metaplasia, and columnar cells with basophilic mucin were
significantly associated with HepPar1 antibody
immunoreactivity (P ≤ .01). The association between HepPar1 antigen
expression and the presence of squamous mucosal islands,
Paneth cells, and crypt disarray/atrophy was not statistically
significant. The clinical and endoscopic features of the 24
SBE cases with HepPar1 antigen expression are summarized
in ❚Table 3❚.
❚Image 2❚ A, Barrett esophagus with low-grade dysplasia (H&E, ×200). B, Hepatocyte paraffin 1 (HepPar1) antigen expression
is lost in areas of low-grade dysplasia (×200). C, Barrett esophagus with focal high-grade dysplasia (H&E, ×200). D, HepPar1
antigen expression is lost is areas of high-grade dysplasia (×200).
❚Image 3❚ A, Example of a case “suspicious” for Barrett
esophagus (SBE) with “BE-associated” morphologic feature of
multilayered epithelium (arrow; arrowhead [inset]). Additional
features included squamous mucosal islands and pancreatic
metaplasia (not shown) (H&E, ×200). B, Expression of
hepatocyte paraffin 1 (HepPar1) antigen is detected (×200). C,
SBE case with BE-associated morphologic features of crypt
disarray/atrophy, squamous mucosal islands (asterisks), and
pancreatic metaplasia pictured (arrow) (H&E, ×200).
Clinical information and follow-up distal esophageal
biopsy specimens were available for 14 of 65 cases in the SBE
category, 4 of which demonstrated HepPar1 antigen expression
on the initial biopsy. The median follow-up period was 3 years
(range, 0-9 years), and 1 of 14 patients had diagnostic
histologic features of BE (IM with goblet cells) on repeated biopsy. In
addition, 1 case with the BE-associated features of multilayered
epithelium and pancreatic metaplasia still had these features on
repeated biopsy. The remaining 12 cases demonstrated
squamous mucosa without columnar/glandular mucosa.
The incidence of esophageal adenocarcinoma continues
to increase,27 and earlier cancer detection through endoscopic
surveillance with biopsies provides a significant survival
advantage vs diagnosis after symptomatic presentation.7,28,29
Identification of at-risk patients who could benefit from early
follow-up is made through the histologic diagnosis of BE,
the precursor lesion of dysplasia and esophageal
adenocarcinoma. Currently, the histologic diagnosis of BE requires the
demonstration of unequivocal goblet cells by H&E staining
within distal esophageal biopsy specimens.7 However, goblet
cells are not always apparent, and perhaps more important,
this morphologic feature may not be the earliest sign of
intestinal differentiation.2,11 Thus, recognition of suspicious
morphologic features and the judicious use of biomarkers that
can detect this metaplastic state may be important for clinical
For decades, the use of different histochemical stains and
immunohistochemical markers for the evaluation of IM in
esophageal biopsy specimens has been studied.8,30 Periodic
acid–Schiff/alcian blue, pH 2.5, stains neutral and acidic
cytoplasmic mucins of goblet and nongoblet columnar epithelium.
However, several authors have noted nonspecific staining
© American Society for Clinical Pathology
Anatomic Pathology / Original Article
❚Image 3❚ D, Expression of HepPar1 antigen is detected
(×200). E, SBE case with multilayered epithelium
(arrowheads), columnar cells with blue mucin (arrows), and
pancreatic metaplasia (asterisk) (H&E, ×200). F, Granular,
cytoplasmic HepPar1 antigen expression is present in
columnar cells adjacent to or within morphologic features
with periodic acid–Schiff/alcian blue, including staining of
foveolar and glandular epithelium of the cardia and distal
esophagus, which can potentially lead to a false-positive BE
Several immunohistochemical markers have been used as
potential indicators of intestinal differentiation in esophageal
columnar epithelium with and without goblet cells,
including MUC2, villin, Cdx-2, and Das-1.2,9,11,13,14,24 The MUC2
antibody reacts with the mucin in goblet cells; therefore, the
staining intensity depends on the density of goblet cells,
indicating that this marker may not be a reliable marker of early
The antibody to villin (a cytoskeleton protein in the
microvillus core of the brush border) is a less specific marker
for IM, as it can also be reactive within fundic-type mucosa.11
However, in a study by Shi et al,11 cytoplasmic expression
of villin in columnar-lined mucosa without goblet cells was
proposed as a sign of early intestinal differentiation.
Clinical and Endoscopic Features for 24 Cases “Suspicious”
for Barrett Esophagus With Hepatocyte Paraffin 1 Antigen
Age, mean (range) y
Endoscopy findings suspicious
for Barrett esophagus†
* Data are given as number (percentage) unless otherwise indicated.
† Suspicious findings included a proximally displaced squamocolumnar junction, an
irregular Z-line, and salmon-colored mucosa.
Phillips et al13 demonstrated that goblet and non–goblet
cells in 100% of BE cases studied exhibited nuclear
immunoreactivity for antibody to Cdx-2 (a transcription factor
involved in intestinal epithelial differentiation and
maintenance). That study also demonstrated that 30% of cases with
junctional-type esophageal epithelium with no suspicion of
IM were focally Cdx-2+, which was postulated to represent
evidence of early intestinal differentiation as opposed to lack
In a study by Glickman et al,15 Das-1 (a monoclonal
antibody developed against a colonic epithelial protein) was
detected in 88% or more of BE cases with reactivity in 35% of
cases of junctional-type epithelium without IM. While some
of these markers proved highly sensitive and/or specific for
BE, none of these studies specifically evaluated expression
in cases that lacked goblet cells but were morphologically
suspicious owing to the presence of BE-associated histologic
features. Ours is the first study to systematically evaluate
HepPar1 antigen expression as a marker of intestinal
differentiation in the nongoblet columnar epithelium of distal esophageal
biopsy specimens with BE-associated morphologic features.
Several studies have revealed that HepPar1 antigen
(CPS1) is expressed in small intestinal mucosa but not in
normal esophageal, gastric, or colonic mucosa, which varies
from other markers (ie, MUC2, villin, Cdx-2, and Das-1)
previously used in the evaluation of BE.1,18 Unlike MUC2
antibody, for which the staining intensity depends on the density
of goblet cells, HepPar1 antigen is expressed in the absorptive
cells and may be detected in samples with IM even if goblet
cells are rare or not present in a particular section.1 Unlike
villin, which may be expressed in fundic-type mucosa, HepPar1
was not found to be expressed in gastric mucosa.1,18 HepPar1
antigen is expressed in the complete and incomplete forms of
IM and in focal and diffuse IM, which potentially makes
HepPar1 antibody a useful tool in small biopsy specimens.1 Cdx-2
and Das-1 have been found to be expressed in 30% and 35%,
respectively, of esophageal biopsy specimens demonstrating
junctional epithelium without goblet cells or suspicion of
IM.13,15 These findings may support evidence of early
intestinal differentiation, but could support lack of specificity.
In our study, all cases diagnosed as BE (with endoscopic
features and histologically unequivocal goblet cells)
demonstrated HepPar1 antibody immunoreactivity. Of the cases that
were designated as SBE on histologic grounds, HepPar1
antigen expression was present in 37% with 2 or more described
BE-associated morphologic features, 59% with 3 or more
BEassociated morphologic features, and 100% with 4 or more
BE-associated morphologic features. These results indicate
that identification of increasing numbers of BE-associated
morphologic features correlates with a greater likelihood of
HepPar1 antigen expression, supporting the presence of IM.
Granular cytoplasmic immunoreactivity in columnar cells
was typically present in the vicinity of the described
BEassociated features, implying that these histologic features
do not necessarily equal IM, but rather indicate that the
tissue displays intestinal differentiation, despite the absence of
identifiable goblet cells. Only 4 of the RE cases had focal
HepPar1 antibody immunoreactivity, of which 2
demonstrated 1 BE-associated morphologic feature and endoscopic
findings suspicious for BE. Of the 110 non-BE cases, only 2
(1.8%) expressed HepPar1 antigen without the presence of at
least 1 BE-associated feature. HepPar1 antigen expression is
uncommonly identified in cases without morphologic changes
that are associated with intestinal differentiation. It is
interesting that, similar to findings by Chu et al,1 HepPar1 antigen
expression was lost in areas of adjacent low-grade dysplasia,
high-grade dysplasia, and adenocarcinoma. The loss of
HepPar1 antigen expression with development of dysplasia or
malignant expression is not an event unique to the esophagus.
Loss of antigen detection has been described in poorly
differentiated hepatocellular carcinomas, IM-associated gastric
adenocarcinomas, and small intestinal adenomas with
highgrade dysplasia and/or invasive adenocarcinoma.1,18,36
There is ongoing debate about the clinical significance
of detecting non–goblet cell forms of IM. Do they carry the
same risk of progression to dysplasia and/or adenocarcinoma?
According to the British Society of Gastroenterology, an
endoscopically abnormal area suggestive of BE proximal to
the GEJ with biopsy findings of columnar-lined mucosa is
enough to diagnose BE regardless of the presence of goblet
cells.37 Several studies supporting the British Society of
Gastroenterology guidelines have concluded that nongoblet
columnar epithelium may have neoplastic potential, and
people who have specialized columnar mucosa without goblet
cells have a similar risk of neoplastic progression as do people
with goblet cells.12,16,38 Bright et al39 found a 2.5% incidence
of significant findings (high-grade dysplasia or
adenocarcinoma) in a 3-year endoscopic surveillance study of patients
who had endoscopic abnormalities suspicious for BE with
columnar-lined mucosa with or without goblet cells.
Currently, the American Society for Gastrointestinal
Endoscopy guidelines state that screening endoscopy for BE
may be appropriate in patients with gastroesophageal reflux
disease symptoms, but no further screenings are necessary
after a negative examination.40 It is interesting that Gatenby
et al38 reported that up to 40% of cases of BE in their study
would have been missed based on initial biopsy using the
current American Society for Gastrointestinal Endoscopy
criteria. They further reported that 54.8% and 90.8% of patients
with non–goblet cell columnar metaplasia demonstrated IM
at 5 and 10 years of follow-up, respectively.38 A limitation
of our study is the lack of long-term follow-up and adequate
rebiopsy samples, given the initial diagnosis of RE. The
median follow-up period for the 65 patients in our SBE category
was 3 years (range, 0-9 years). Although 14 patients
underwent rebiopsy, only 2 had adequate squamocolumnar junction
samples, 1 of which contained diagnostic goblet cells of BE.
There is great importance in making a diagnosis of BE
for an individual patient, as patients with BE have reportedly
© American Society for Clinical Pathology
higher psychological stress and financial burden than the
general population.10 However, BE remains the major risk factor
for the development of esophageal dysplasia and
adenocarcinoma.1-7,10 Mortality from esophageal cancer is high, and
there is a significant survival advantage with early cancer
detection vs symptomatic presentation.7,10,28,29
Currently in the United States, the identification of
goblet cells in distal esophageal biopsy specimens is the only
histologic criterion used to diagnose BE and initiate
followup screening. At times, the diagnosis of BE can be difficult
to make on H&E-stained slides because of inconspicuous
or rare goblet cells, sampling error, or goblet cell
mimickers. Based on our results, recognition of the well-described
BE-associated morphologic features predicts the presence of
HepPar1 antigen expression, a sensitive and specific marker
of IM. The presence of certain morphologic features
(specifically multilayered epithelium, pancreatic metaplasia, and
columnar cells with blue mucin) and overall 2 or more of the
proposed BE-associated morphologic features were
significantly associated with HepPar1 antigen expression. No
longterm follow-up studies or surveillance guidelines of patients
with clinicopathologic features suspicious for BE but without
diagnostic goblet cells exist. However, one could argue that
given the evidence of metaplastic change, reported increased
neoplastic risk, and the need for early cancer detection,
recognition of these earlier/non–goblet cell lesions is important,
as opposed to implying a completely negative screening. Use
of the clinical impression, the presence of these suspicious
morphologic changes, and possibly phenotypic markers of
intestinal differentiation may prove to be an additional method
of diagnosing IM of the distal esophagus as opposed to the use
of goblet cells alone.
From the Departments of 1Pathology, Immunology and
Laboratory Medicine and 2Epidemiology and Health Care Policy,
University of Florida College of Medicine, Gainesville; and
3Pathology, Duke University Medical Center, Durham, NC.
Supported in part by the Clinical Research Committee,
Department of Pathology, University of Florida. Dr Liu is
supported by grant K26RR023976 from the National Institutes of
Health, Bethesda, MD.
Address reprint requests to Dr Cardona (diana.cardona@
duke.edu) or Dr Liu ().
* Drs Liu and Cardona share senior authorship.
Acknowledgments: We thank Lizette Vila, MD, and Shannon
McCall, MD, for manuscript review and Elaine Dooley, MT, for
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