Mimics in Gastrointestinal Pathology
Case 5 -
Allergic / Eosinophilic Esophagitis Versus Reflux Esophagitis
Alyssa Krasinskas, Jeffrey Goldsmith and Susan Abraham
The attached photomicrographs were taken from two esophageal biopsies obtained from a 15 year old boy
with a 6 month history of intermittent severe epigastric, burning pain that often radiated to his back.
The patient reported that the pain seemed to be worse at night, and was exaggerated by ingestion of
certain foods, such as orange juice, sodas, and chocolate.
Due to the severe nature and the length of the patient's symptoms, his primary care physician referred
him to a gastroenterologist who was similarly concerned. An upper endoscopy was performed. The duodenum
and stomach were grossly normal. However, the esophageal mucosa appeared pale with red streaks; these
findings were most prominent in the distal 5 cm; the proximal esophagus appeared normal. The endoscopist
biopsied the pale area at 38 cm (figures 1-3) and the proximal esophagus at 20 cm (figures 4-6).
The biopsy at 38 cm shows squamous mucosa with marked epithelial regenerative changes as the
epithelial cells exhibit increased nuclear to cytoplasmic ratio throughout the entire thickness of the
epithelium. Examination at higher power shows markedly increased numbers of intraepithelial eosinophils
with up to 50 per high power field. Additionally, there are aggregates of 3-5 eosinophils in the
superficial epithelium (termed 'eosinophilic microabscesses'), extensive eosinophilic degranulation, and
increased density of eosinophils in the superficial epithelium compared with the basal epithelial cells.
The biopsy at 20 cm, however, showed markedly decreased number of intraepithelial eosinophils, up to
10 per high power field, compared with the distal biopsy. The regenerative epithelial changes seen in
the proximal biopsy were absent; also, there were no eosinophilic microabscesses. Mild amounts of
eosinophilic degranulation were seen.
Based on these findings the following diagnoses were rendered:
Note: The distal biopsy shows up to 50 intraepithelial eosinophils per high power field with
extensive eosinophilic degranulation, eosinophilic microabscesses, and increased density of eosinophils
towards the luminal aspects of the epithelium. These features suggest allergic / eosinophilic
esophagitis, however the marked decreased number of eosinophils in the proximal biopsy (up to 10
eosinophils per high power field) also raises the possibility of reflux esophagitis. Clinical
correlation is required to make this distinction.
- Esophagus, 38 cm, biopsy:
- Moderately active esophagitis; see note.
- Esophagus, 20 cm, biopsy:
- Mildly active esophagitis; see note.
The patient was started in high-dose proton pump inhibitors. Within one month, his symptoms
disappeared. The patient was given a diagnosis of severe reflux esophagitis.
Background & Pathogenesis:
In a recent comprehensive review and consensus recommendation statement, Furuta et al., defined
allergic / eosinophilic esophagitis (EE) as "a clinicopathologic disorder of the esophagus characterized
by esophageal and/or upper gastrointestinal tract symptoms in association with esophageal mucosal biopsy
specimens containing more than or equal to 15 intraepithelial eosinophils / high power field (HPF) in one
or more biopsy specimens and absence of pathologic gastroesophageal reflux disease (GERD) as evidenced by
a normal pH monitoring study of the distal esophagus or lack of response to high-dose proton pump
inhibitor (PPI) medication
The epidemiologic characteristics of EE remain somewhat unknown. However, it is clear that EE more
often affects males in both the pediatric and adult populations with up to 75% of EE patients being
Few studies have been performed that addressed the incidence and/or prevalence of
disease; however, in a study performed on the population in Hamilton County, Ohio, the incidence of EE
was up to 1.7 / 10,000 persons and the prevalence of disease was up to 3 / 10,000 people ; in
longitudinal studies, the prevalence of disease has been noted to be increasing . This is
likely due to increasing recognition of disease; additionally, since EE is not associated with mortality,
the prevalence of disease is expected to increase with time. It seems that there is significant ethnic
variation in the distribution of EE with a majority of cases reported in Caucasians; however this topic
has not been extensively studied.
Unlike long-standing GERD, which has an association with the development of Barrett's esophagus,
dysplasia, and adenocarcinoma, a long history of EE predisposes patients to esophageal mural fibrosis
that results in stricture formation
These patients with strictures are more likely to
suffer from dysphagia and food impaction. To date, an association with neoplasia has not been observed.
The pathogenesis of EE remains relatively unclear. However, it is relatively certain that EE is an
allergic disease since most patients have a history of environmental hypersensitivity as evidenced by
positive RAST testing and/or positive skin prick testing . Additionally, changes identical
to EE can be reproduced in mouse models by exposing the animals to various allergens after
sensitization . It also seems that EE is associated with cytokines secreted by TH2
lymphocytes that directly act on and recruit eosinophils. These cytokines include IL-4, IL-5, and IL-13
and their secretion may act to recruit eosinophils to the squamous epithelium via the secretion of
eosinophil-specific chemokines, the eotaxins, in appropriately stimulated hosts
Additionally, there has been an association with a single nucleotide polymorphism of the eotaxin-3
gene . However, this genetic mutation has not been causally associated with the development
of EE, and may predispose patients to the development of EE.
Diagnosis of Eosinophilic / Allergic Esophagitis:
Clinical Findings & Laboratory Studies:
Classically, symptoms of EE closely mimic GERD, with substernal chest pain and referred pain to the
back being common symptoms in both children and adults. However, dysphagia is the most frequent symptom
in patients with EE in adults. Food impaction is also closely associated with EE, and was seen in 50% of
patients in one case series of adult patients . In children, feeding intolerance, failure to
thrive, and vomiting can also be seen .
Intraesophageal pH probe monitoring is considered the gold standard for the diagnosis of acid reflux.
In the early studies of EE, pH probe studies were performed to exclude GERD, and are negative in up to
80% of adult and pediatric patients with EE
However, the current standard of care is to
give patients a trial of proton-pump inhibitors to exclude GERD. If patients respond to this treatment,
GERD is the presumed diagnosis .
Endoscopically, a host of abnormal findings can be seen which include pale mucosa, white exudates,
longitudinal furrows, strictures, and 'crepe paper esophagus'. The presence of multiple, transient
mucosal rings, termed 'feline esophagus,' has also been reported in EE. Of these findings, the presence
of longitudinal furrows and 'crepe paper' changes, in which the esophageal mucosa becomes pale and
fragile-appearing, are most suggestive of EE
However, none of these findings is
In general, biopsy findings in patients with EE include reactive squamous epithelium, increased length
of the submucosal papillae, and significant numbers of intraepithelial eosinophils. The intraepithelial
eosinophils number in excess of 15 eosinophils per high-power field, and are typically distributed
preferentially toward the luminal 1/2 or 1/3 of the squamous epithelium
extensive eosinophilc degranulation  and collections of over 4 eosinophils, typically present
in the superficial epithelium, termed 'eosinophilic microabscesses,' can be seen in EE .
Perhaps the most specific finding of EE is the presence of a superficial exudate of fibrin, eosinophils,
and eosinophilic debris that is adherent to the epithelial surface; however, this finding is uncommonly
seen. The distribution of eosinophilic inflammation along the esophageal length is typically uniform
with similar numbers of intraepithelial eosinophils in both proximal and distal esophageal biopsies
. Lamina propria, when present, may show increased fibrosis
Major mimic: Gastroesophageal reflux disease
Gastroesophageal reflux disease can closely mimic EE. The histologic overlap between GERD and EE is
sufficient such that a definitive pathologic diagnosis of EE or GERD should never be made when over 15 intraepithelial eosinophils per hpf are seen in any
biopsy . Rather, a description of the histologic findings should be given and an appropriate
differential diagnosis should be delineated(see index case above). In general, however, the following
histologic findings help to separate EE from GERD:
1. Numbers of intraepithelial
eosinophils: EE generally has over 15-20 intraepithelial eosinophils per high-power field, whereas
biopsies of GERD typically have substantially less than this number. When using this criterion, one
should report the maximal number of eosinophils seen in a particular biopsy, not the average.
2. Distribution of eosinophils
along the esophagus: When well-informed clinicians suspect EE based on clinical findings or the
endoscopic appearance, they usually take biopsies from both the distal and proximal esophagus. In cases
of GERD, the intraepithelial eosinophilia is most often exclusively present in the distal biopsy. If
eosinophils are present in proximal biopsies, there are significantly reduced in number when compared to
the distal biopsy. In cases of EE, the numbers of intraepithelial eosinophils remains relatively
constant throughout the entire length of the esophagus.
3. Distribution of eosinophils
throughout the epithelial thickness: In EE, the eosinophils show increased density towards the
luminal aspect of the epithelium. Whereas, in GERD eosinphils are distributed evenly throughout the
microabscesses: Aggregates of more than 4 intraepithelial eosinophils within the superficial
epithelium are more highly associated with EE.
degranulation: Typically, biopsies of patients with EE show, sometimes extensive, eosinophilic
degranulation. This is much less commonly seen in GERD. There is some recent evidence, however, that
artifactual eosinophilic degranulation may be induced by biopsy procurement and/or manipulation of the
biopsy specimen at the grossing bench
6. "Eosinophilic Exudate":
The presence of an adherent exudate composed of eosinophils, eosinophilic debris, and fibrin seems to be
the most specific finding for the diagnosis of EE. However, this assertion requires further study.
Sadly, however, this seems to be a specific, but not sensitive criterion.
Although GERD is the most common mimic of EE, other esophagitides also enter the differential
diagnosis. Other inflammatory conditions that may induce an eosinophilic response include the following:
1. Infections : While the
inflammatory infiltrate in infectious esophagitis typically is composed of neutrophils, eosinophils can
sometimes predominate. In these cases, the finding of the infectious organism, most commonly Candida pseudohyphae, would obviously help to arrive at the correct diagnosis.
Other infectious organisms that might induce an inflammatory infiltrate composed partly of eosinophils
include herpes simplex virus, and, less commonly, cytomegalovirus. Again, the finding of neutrophils
within the inflammatory infiltrate should prompt a thorough search for an infectious etiology
It is important to note that Candida esophagitis and EE can
be coincident, since the main treatment for EE is topical steroid therapy which predisposes patients to
2. Crohn's Disease: Crohn's
disease uncommonly involves the esophagus. Biopsies of esophageal involvement by Crohn's disease
typically show ulceration with a brisk lymphocytic infiltrate; non-necrotizing granulomas are rarely
seen. In a minority of cases, eosinophils may be a minor constituent of the infiltrate .
3. Other diseases: For
completeness sake, other diseases, such as chemical induced esophagitis, radiation damage, drugs,
graft-versus-host disease, and various connective tissue diseases may cause eosinophilic inflammation in
the esophagus. In these rare cases, the eosinophilic infiltrate is typically found in combination with
other findings that lead to the correct diagnosis. For example, in radiation-induced esophagitis, the
epithelium may contain a polymorphic infiltrate, including eosinophils. However, the submucosal tissue
would contain the vascular changes, and atypical stromal cells typical of radiation-induced esophagitis.
Eosinophilic/allergic esophgitis is typically treated with topical steroid therapy. Patients orally
instill topical steroids from a metered dose inhaler. Instead of inhaling this preparation, patients
swallow it. This action coats the esophageal mucosa with steroids which decreases the intraepithelial
inflammation. Little of this swallowed steroid is absorbed systemically. Using this therapy, all
patients studied to date have had a significant decrease in their symptoms, and about 75% of patients had
complete symptomatic resolution
Other treatments include systemic corticosteroids and
dietary therapy. Systemic corticosteroids are not typically used due to long-term systemic side
effects. However, if patients present with severe symptoms of EE, systemic corticosteroids may be used
on a short-term basis to relieve acute symptoms. Institution of a food elimination diet has had variable
success in the treatment of EE. However, the use of an amino acid-based diet is quite effective in
treating EE with up to 98% of patients responding to this treatment modality . However,
this treatment is quite expensive and often requires installation through a nasogastric or percutaneous
gastrostomy tube because the amino-acid based diet is unpalatable.
Figure 1: Esophageal biopsy at 38 cm. At low power, the squamous epithelium appears regenerative
with increased nuclear to cytoplastic ratio throughout the entire thickness of the epithelium.
Figure 2: Esophageal biopsy at 38 cm. At intermediate power, the a dense eosinophilic infiltrate is
appreciated. At this power, the density of the eosinophils increases towards the luminal aspect of the
Figure 3: Esophageal biopsy at 38 cm. At high power, approximately 50 eosinophils are seen. There
are few clusters of 3-5 eosinophils present in the superficial epithelium. Also, significant
eosinophilic degranulation is present.
Figure 4: Esophageal biopsy at 20 cm. At low power, the epithelial reactive change seen in the
distal biopsy is not seen.
Figure 5: Esophageal biopsy at 20 cm. At intermediate power, the numbers of intraepithelial
eosinophils is significantly reduced compared to the distal biopsy. These eosinophils are present singly
and are disbursed evenly throughout the thickness of the epithelium.
Figure 6: Esophageal biopsy at 20 cm. At high power, there are only 8-10 intraepithelial eosinophils
per field . No eosinophilic microabscesses are seen, and there is minimal eosinophilic degranulation.
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