THE ENDOSCOPICALLY ABNORMAL ESOPHAGUS Gastroesophageal Reflux Disease
THE ENDOSCOPICALLY ABNORMAL ESOPHAGUS
The endoscopic abnormalities that may be seen in association with esophageal disorders
are numerous, varying from subtle alterations in the esophageal mucosal surface to large ulcers
or masses. This discussion will be focused on a few commonly encountered entities in which
clinical, endoscopic and histologic correlation are critical for establishing a correct diagnosis.
These include gastroesophageal reflux disease (GERD), eosinophilic esophagitis and Barrett¡¯s
esophagus.
Gastroesophageal Reflux Disease
The most recent practice guidelines for diagnosis and management of gastroesophageal
reflux disease support establishing a presumptive diagnosis of GERD without endoscopic
evaluation in the setting of typical symptoms such as heartburn and regurgitation (1). Empiric
medical therapy with a proton pump inhibitor is recommended; therefore, most patients that are
being evaluated for GERD endoscopically are already on PPI therapy at the time of biopsy.
Endoscopic examination is recommended in any patient with ¡°alarm¡± symptoms, or in those at
high risk for development of complications. Alarm symptoms include dysphagia, non-cardiac
chest pain, or a lack of a response to PPI therapy. Although the presence of GERD-related
symptoms does not provide a high level of sensitivity or specificity for predicting esophageal
abnormalities on upper endoscopy, it may be reasonable to screen select individuals for Barrett¡¯s
esophagus by endoscopy. Epidemiologic risk factors for BE have been well established and
include age over 50, symptoms for > 5-10 years, obesity, and male sex. Recent data suggest that
selectively screening patients that fall into this high risk group may be reasonable (2).
The endoscopic appearance of the esophagus varies with disease severity.
Approximately one third of patients with chronic GERD symptoms are endoscopically normal
(3). Areas of patchy erythema and red streaks are the first endoscopic abnormalities. Later
erosions and ulcers develop; these predominate distally and taper off proximally. As the disease
progresses, the ulcers become confluent, even circumferential. Strictures or BE characterize
severe chronic disease. Several endoscopic classifications have been developed to evaluate the
esophageal mucosa. The two most common are the Savary-Miller MUSE system and ¡°Los
Angeles¡± classifications (4,5). The use of these grading systems among gastroenterologists
varies, likely depending on the practice setting. Among esophageal biopsies seen in our practice
in 2010, 27.9% included an LA grade, and 12.2% a Savary-Miller grade (6).
Savary-Miller Classification
Grade
I
II
III
IV
Features
One or more supravestibular reddish spots with or without exudates
Erosive and exudative lesions in the distal esophagus that may be confluent, but not
circumferential
Circumferential erosions in the distal esophagus covered by hemorrhagic and
pseudomembranous exudates
Presence of chronic complications such as deep ulcers, stenosis, or scarring with
Barrett¡¯s metaplasia
Los Angeles Classification
Grade
A
B
C
D
Features
One or more mucosal breaks ¡Ü 5 mm in length
At least one mucosal break > 5 mm long, but not continuous between the tops of
adjacent mucosal folds
At least one mucosal break which is continuous between adjacent mucosal folds, but
not circumferential (< 75% of periphery)
Mucosal breaks that involve at least three-quarters of the luminal circumference
Note: Ulcers, strictures, Barrett¡¯s metaplasia, and other findings are reported as an adjunct to each grade.
Reflux Esophagitis
GERD affects patients of all ages, even children and small infants, but is most common
among patients over age 65 (7). GERD affects from 3% to 4% of the population, and its
incidence has increased in the past few decades. The annual cost of managing the disease in the
United States is estimated at 9 billions dollars (8). GERD is equally present among men and
women, but there is a male predominance of esophagitis and Barrett esophagus. GERD affects
whites more frequently than members of other races.
Conditions predisposing to GERD include smoking, decreased physical activity,
increased intra-abdominal or intragastric pressure, including pregnancy, ascites, body mass index
and obesity; and delayed gastric emptying. Postmenopausal estrogen therapy has been
associated with GERD symptoms (9, 10). Motility disorders including diabetes, alcoholic
neuropathies, and scleroderma also predispose to GERD. Patients with hiatal hernias and
strictures are especially prone to develop GERD. It also follows surgical procedures.
Clinical Features
Transient mild reflux affects most individuals including children and adults. The degree
of reflux must be severe for individuals to become symptomatic. Adults present with diverse
symptoms including heartburn, regurgitation, bitter-tasting fluid in the mouth, dysphagia,
odynophagia, nausea, vomiting, hiccups, anginalike chest, and hoarseness. The regurgitation can
cause a spectrum of conditions, including asthma, chronic cough, chronic laryngitis or
pharyngitis, subglottic stenosis, and dental disease. Rare patients present with bleeding from
esophageal ulcers. Complications peak between ages 50 and 70 years (11).
As discussed above, the majority of patients with GERD symptoms are treated with
proton pump inhibitor (PPI) therapy, often prior to being seen by a gastroenterologist (12). A
recent survey found, however, that as many as 40% of patients receiving PPI treatment have
residual symptoms (13). As a result, many of the patients undergoing endoscopy and biopsy for
GERD symptoms are those that are refractory to PPI therapy. Such patients may have additional
disorders superimposed on GERD. The differential diagnosis of esophageal disorders that may
be associated with refractory symptoms in patients treated with PPIs is summarized below.
Disorders Associated with Residual Symptoms in Patients Treated with PPIs
Esophageal Disorders
Reflux Related
Incorrect medication dose timing
Medication non-compliance
Residual pathologic acid secretion
Rapid PPI metabolism
Hypersecretory state
Anatomic abnormalities
Defective LES function
Hypersensitivity of esophagus to small amounts of refluxed material
Non-reflux related
Achalasia
Esophageal spasm
Scleroderma
Eosinophilic esophagitis
Pill esophagitis
Infectious esophagitis
Non-Esophageal Disorders
Gallbladder disease
Cardiovascular disease
Musculoskeletal disorders
Malignancy (GI and non-GI)
Histologic Features
Biopsies are performed to confirm the diagnosis of GERD; to document complications,
including esophagitis, BE, or tumor development; and to rule out the presence of coexisting
infections. Since esophagitis tends to be a patchy process, it is easy to miss diagnostic changes
on a single biopsy. The current wisdom is that biopsies should be taken in the area just distal to
the Z line to detect carditis (see below), just proximal to the Z line to detect esophagitis, and 3
cm proximal to the Z line to detect the hyperplastic changes that are more predictive of the
presence of GERD than more distally derived biopsies.
Various histologic features should be assessed when examining the biopsy for GERD
(see below). No single feature represents an absolute criterion for the presence of GERD, but
each is helpful in establishing the diagnosis. In the absence of a known drug history or the
presence of specific microorganisms, biopsies, particularly distal biopsies showing esophagitis,
are most likely to be due to GERD.
Epithelial Hyperplasia
The normal basal cell layer is only one to four cells high; it should not constitute more
than 15% of the epithelial thickness. In the setting of GERD, the basal zone increases from 10%
to more than 50%; papillary height can increase to more than 50% to 75% of the total epithelial
thickness (14). This change affects patients with an endoscopically normal mucosa as well as
those with endoscopic evidence of esophagitis. Regenerative changes are characterized by
nuclear enlargement, hyperchromasia, and mitoses that remain limited to the basal layer.
Prominent nucleoli may be present.
Although recognition of the basal layer of the squamous epithelium is not difficult,
determination of its uppermost limit often is. One definition that may be helpful (15) is that the
upper limit of the basal zone is that point where the majority of epithelial cell nuclei are
separated by a distance less than the diameter of one nucleus. In addition, accurate assessment of
the thickness of the basal layer requires evaluating well-oriented specimens. The basal height
should not be assessed near vascular papillae. It may be helpful to divide the epithelial thickness
into thirds. When the lower third is divided in half, the basal cells should be confined to its
lower half. In less optimally oriented specimens, basal zone thickness can be evaluated if one
sees at least three to four papillae arranged in parallel to one another and not cut tangentially. In
tangentially cut sections, a helpful feature is an increase in the number of papillae, which can be
evaluated in an en face section. In this setting one may see overlapping capillaries. Since the
biopsies may be small or have minimal or no lamina propria or they may be inappropriately
oriented and therefore difficult to evaluate for basal hyperplasia and papillary elongation, we
recommend that the biopsies be examined at three levels to increase their diagnostic accuracy.
The sensitivity of hyperplasia as a diagnostic feature of GERD is only 60% to 70% (16).
Basal cell hyperplasia is a reversible change that disappears with treatment. Hyperplasia also
complicates other forms of esophagitis so that it is not specific for GERD.
Papillary Height
Papillary elongation is most often defined as papillae extending more than two-thirds of
the distance to the epithelial surface. The degree of papillary elongation correlates with severity
of reflux (17), but is not a specific feature of GERD. Evaluation of papillary height, like basal
layer thickness, requires a well-oriented biopsy in which the entire thickness of the epithelium is
visible.
Dilated Intercellular Spaces
Dilated intercellular spaces occur in patients with both erosive and non-erosive GERD
(18-20). In light microscopic studies, dilated intercellular spaces are defined as an increase in
the distance between squamous epithelial cells. This distance varies from greater than 0.47 to
2.4 um depending on the study (18-22). Dilated intercellular spaces are seen predominantly in
the basal layer, and are thought to occur as a result of stretching and detachment of desmosomes
(20). The prevalence of dilated intercellular spaces in biopsies from patients with GERD ranges
from 67-94% depending on whether or not clinical symptoms, endoscopically identifiable lesions
or pH monitoring abnormalities are present (23).
Inflammation
Intraepithelial lymphocytes. Small numbers of lymphocytes populate both the normal mucosa
and the lamina propria so that their presence does not aid in making a diagnosis of esophagitis.
However, they are very conspicuous in patients with GERD (24). Biopsies with esophagitis
average greater than six lymphocytes per hpf (25). They are part of the inflammatory response
in GERD but are not an independent marker of reflux esophagitis.
Neutrophils. The presence of isolated neutrophils, either in the squamous epithelium or in the
lamina propria, serves as evidence for acute esophagitis of many etiologies, and are most
commonly observed in erosive GERD. Neutrophils are present in the epithelium of from 1040% of patients with reflux esophagitis, making them a relatively insensitive marker (26-28).
They tend not to appear until the inflammation becomes severe and the epithelium ulcerated.
They generally decrease in number the further one goes away from the erosion or ulcer. When
numerous neutrophils are identified in an esophageal biopsy, the possibility of other ulcerating
conditions including infection and pill-mediated injury should be considered.
Eosinophils. The normal number of eosinophils present in the esophagus is still somewhat
controversial. However, many feel that eosinophils are normally absent (26, 29). Some,
however, have found a modest number (usually less than 5 per high power field) may be seen
(27). It is likely that these differences arise from differing definitions of normal controls versus
GERD. Influx of eosinophils into the epithelium occurs early in the course of reflux esophagitis
and may be seen in the absence of basal cell hyperplasia. Other causes for mucosal eosinophilia
include the entities listed in the Table below.
Eosinophil-Associated Esophageal Disorders
Primary eosinophilic disorders
Eosinophilic esophagitis
Secondary eosinophilic disorders
Eosinophilic gastroenteritis
Hypereosinophilic syndrome
Secondary noneosinophilic disorders
Infection
Pill esophagitis
Gastroesophageal reflux disease
Tumors
Vasculitis
Connective tissue disorders
One can easily appreciate eosinophils in small endoscopic biopsies, even when the
biopsies are not well oriented. They affect up to 60% of adults with severe disease but the
intraepithelial eosinophils may be focal in nature, necessitating a search for them on serial
sections; their presence does not correlate with disease severity (29, 30). Eosinophils are not a
sensitive marker for GERD, since they are only found in 40% to 50% of individuals with GERD
(23, 28, 30). Significant esophageal eosinophilia (>15 intraepithelial eosinophils per hpf) may
sometimes be seen in patients with GERD, but should prompt the pathologist to consider the
diagnosis of eosinophilic esophagitis as discussed later.
Erosions and Ulcers in Gastroesophageal Reflux Disease
The mucosal changes of reflux esophagitis range from the changes already described to
acute esophagitis, erosions and superficial ulcers. The epithelium close to erosions or ulcers
often contains neutrophils, eosinophils, and many lymphocytes. The erosions or ulcers often
contain granulation tissue, an inflammatory exudate, and fibrinoid necrosis in the ulcer base.
Lymphoplasmacytic infiltrates, often forming lymphoid aggregates, tend to cluster around
erosions and ulcers. Epithelium at the ulcer margin is usually attenuated. Marked basal cell
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