Diagnostic Problems in GI Pathology
Case 3 -
Eosinophilic Disorders of the Gastrointestinal Tract
Lisa Yerian, John Hart and Amy Noffsinger
The diagnosis of gastrointestinal diseases characterized by an increased number of eosinophils is
challenging for several reasons: 1) the eosinophilic infiltrates are often quite patchy, making sampling
error an important consideration; 2) eosinophils may infiltrate any bowel layer, and thus may be missed
in mucosal biopsy specimens; 3) the normal range for eosinophil density in various parts of G.I. tract
have not been well established; and 4) some of the disease states are poorly defined and have overlapping
Recognition of eosinophils is usually not an issue for surgical pathologists, although degranulated
forms may be overlooked. The appearance of eosinophils does vary somewhat depending on the fixative
used – for instance, in Hollande's fixative eosinophils are relatively inconspicuous.
Eosinophil Density in Healthy Individuals
Several studies have quantitated eosinophil number in the rectal mucosa of normal infants that had
undergone suction biopsy to rule out Hirschsprung's disease. In all of the studies there were a mean of
less than 10 eosinophils /hpf. However, single fields with greater than 20 eosinophils were not
uncommon. In an autopsy study of 44 children who died from accidents the mean and median number of
eosinophils in the colonic mucosa was 17/hpf and 14/hpf respectively, with 28% of cases having more than
20/hpf. In a more detailed study of 11 of these autopsies the mean number of eosinophils was found to
vary in different parts of the colon (35/hpf in the cecum, 20/hpf in the ascending colon, 17/hpf in the
transverse colon, 15/hpf in the descending colon, and 10/hpf in the sigmoid and rectum). The number of
eosinophils in the colonic mucosa of adults has not been well studied, but appears to be about the same
as children. However, there does appear to be significant differences based on geographic location
(significantly greater density in New Orleans compared to Boston). It is not uncommon to see individual
eosinophils within crypt epithelium of scattered crypts in healthy individuals of any age.
The number of eosinophils normally present in the mucosa of other parts of the G.I. tract has been
less well documented. One autopsy study indicates that eosinophils are quite rare in the gastric mucosa
(less than 5/hpf), but are more numerous in the small bowel (15-20/hpf).
In the past intramucosal eosinophils were regarded as a nearly pathognomic indicator of
gastroesophageal reflux disease. Recently it was recognized that large numbers of intramucosal
eosinophils and basal cell hyperplasia were sometimes present in biopsies from patients with dysphagia
(rather than heartburn). The esophagus in such patients often exhibited a characteristic endoscopic
appearance, different than that seen with reflux, characterized by a wrinkled or thickened mucosa,
sometimes with circumferential rings, linear furrows, or tiny vesicles. Unlike patients with reflux,
patients with so-called "eosinophilic esophagitis" often had a history of food allergy/asthma/atopy, and
prior food bolus obstruction. Vomiting occurs with equal frequency in patients with eosinophilic
esophagitis and reflux. Although this disorder has only recently recognized, retrospective studies have
shown that in the past cases were mis-diagnosed as severe reflux esophagitis. Treatment with steroids or
an elimination diet is usually effective, but esophageal stricture can develop in refractory cases. The
available data suggest that at least in children, eosinophilic esophagitis is usually a manifestation of
a food allergy. Whether eosinophilic esophagitis should be classified as the esophageal form of
eosinophilic gastroenteritis is a matter of semantics.
Biopsies of the esophagus typically revealed a heavy infiltrate of eosinophils, including clusters of
eosinophils (microabscesses), often near the surface. Basal cell hyperplasia is usually prominent. A
cut-off of 24 eosinophils/hpf has been suggested as useful in distinguishing between eosinophilic
esophagitis and reflux esophagitis, but formal counts are not necessary in daily practice. In most cases
of reflux esophagitis the density of intramucosal eosinophils is less than 7/hpf. The presence of
changes that are equally severe in biopsies from the mid-esophagus and distal esophagus is a useful
finding in making the diagnosis of eosinophilic esophagitis (since reflux changes are typically more
severe distally than more proximally). However, in some cases it is not possible to make a firm
histologic distinction between eosinophilic esophagitis and severe reflux esophagitis. Correlation with
the clinical history (dysphagia versus heartburn) and the endoscopic appearance is often sufficient to
arrive at the proper diagnosis, but 24 hour pH monitoring may be necessary in a few patients.
This diagnosis is appropriate when no cause can be identified for a pathologic accumulation of
eosinophils within the stomach, small bowel, or colon. A work-up must be performed to exclude parasitic
infection, vasculitis, connective tissue disease, inflammatory bowel disease, drug reaction, or
myeloproliferative disorder. In Australia many cases of presumed idiopathic eosinophilic enteritis
actually were shown to be due to infestation by the canine hookworm (Ancylostoma
caninum). Trichinella, Ascaris, Trichuris, and Schistosoma species have also been documented to
cause marked intestinal tissue eosinophilia. The presenting symptoms depend on the portion of the G.I.
tract and the bowel layers that are infiltrated by eosinophils. In general, mucosal infiltration results
in diarrhea, while infiltration of the submucosa and/or muscularis propria produces obstruction and/or
pain. Serosal infiltration can cause peritonitis-like symptoms and ascites. Gastric involvement may
lead to nausea and vomiting or gastric outlet obstruction. Small bowel disease can produce
malabsorption, protein losing enteropathy, occult blood loss, and weight loss. Colonic involvement most
often results in diarrhea. Peripheral blood eosinophilia occurs in less than 50% of patients, and is
typically mild. Patients may or may not have a past history of asthma, atopy or eczema.
The histologic diagnosis of eosinophilic gastroenteritis can be quite difficult. The infiltrate of
eosinophils may involve deep bowel layers not sampled in an endoscopic biopsy. In such patients
laparoscopic full thickness biopsy is necessary. The presence of even an occasional eosinophil in the
muscularis propria or subserosal tissues (in the absence of other findings) is quite rare, and
eosinophilic gastroenteritis is the leading diagnostic consideration in such cases.
In mucosal disease the eosinophilic infiltrates can be quite patchy, thus requiring numerous biopsies
to exclude the diagnosis. Since there is a wide variation in the normal density of mucosal eosinophils
the presence of epithelial destruction by eosinophils (not simply infiltration of single eosinophils) or
infiltration of the muscularis mucosae are very helpful in establishing a firm diagnosis.
As noted above, eosinophils are very uncommon in gastric mucosa. In H.
pylori gastritis scattered eosinophils are seen, but are never a prominent component of the
inflammatory cell infiltrate. NSAID gastritis is very common, typically in the form of focal erosions
within otherwise normal mucosa. In some cases a diffuse reactive pattern is seen instead, with foveolar
hyperplasia and marked mucin depletion, but notably little inflammation. In either pattern eosinophils
are not prominent. Crohn's gastritis is characterized by strikingly focal inflammatory cell infiltrates
(usually a mixture of lymphocytes and neutrophils) with inflammatory destruction of glandular or foveolar
epithelium. Eosinophils may be admixed but are not prominent. Eosinophilic infiltrates are usually very
prominent in cases of gastric involvement by Schistosomiasis, which occurs in patients with latent
infection who become immunocompromised. The larval form of the organism is easily identified in the
H&E stained section, as it is quite large and has refractile borders. Foreign bodies embedded in the
gastric mucosa may also elicit strong eosinophilic reactions.
Gastric involvement by eosinophilic gastroenteritis can be diagnosed only when all of the above
conditions have been ruled out. The diagnosis requires the presence of numerous eosinophils in the
lamina propria, but an exact number has never been established. The presence of epithelial destruction
by eosinophils and/or infiltration by eosinophils into the muscularis mucosa allows much greater
confidence in the diagnosis. In the absence of these two features lamina propria infiltration by
eosinophils would need to be at least focally massive (sheet-like) in order to make the diagnosis.
There are numerous causes of eosinophilic infiltration of the small bowel mucosa. In celiac disease
eosinophils are often a prominent component of the lamina propria inflammatory cell population. Heavy
eosinophil infiltrates are typically present in drug-induced enteritis, and this possibility must be
excluded in every patient before a diagnosis of eosinophilic enteritis is made. Drugs that have been
reported to cause eosinophilic enteritis include: trimethoprim-sulfonamide, L-tryptophan, gemfibrozil,
carbamazepine, and enalapril. Parasitic infection must be ruled out by stool ova and parasite tests,
since the organisms are sometimes not evident in tissue sections. Because lamina propria eosinophils can
be numerous in the small bowel mucosa of healthy individuals, the diagnosis of eosinophilic enteritis
should not be considered unless sheets of eosinophils are evident, or foci of epithelial destruction or
muscularis mucosae infiltration are evident. There may be mild villous blunting in areas of massive
eosinophilic infiltration, but overall villous architecture is usually well maintained. If villous
architectural distortion is prominent the possibility of Crohn's disease should be considered clinically.
A diagnosis of idiopathic eosinophilic gastroenteritis involving the colon is not possible until
several other possibilities have been excluded. Eosinophilic infiltration of the colonic mucosa is
typical in inflammatory bowel disease (ulcerative colitis and Crohn's colitis), but the crypt
architectural distortion seen in IBD does not occur in eosinophilic colitis. Parasitic infection and
drug toxicity (especially NSAIDs) must be excluded on clinical grounds. Again, since the density of
eosinophils in healthy individuals varies greatly, it is difficult to determine a numerical cut-off value
diagnostic of a disease state. Destruction of crypt or surface epithelium or infiltration of the
muscularis mucosae by eosinophils strongly suggests a pathologic condition. In the absence of these
features eosinophils must be at least focally present in sheets in the lamina propria.
Allergic Gastroenteritis and Colitis
Intolerance to peptides from cow's milk or soy milk proteins is not uncommon among bottle fed
infants. The presenting signs and symptoms include rectal bleeding, diarrhea, failure of gain weight,
and vomiting. In severe cases metabolic acidosis may develop due to severe diarrhea and electrolyte
loss. In children more than two years old constipation is the most common symptom. In many patients a
presumptive diagnosis is made and the infant is switched to a soy based formula or hydrolase formula.
Occasionally colonoscopic biopsies are obtained. This disorder can rarely occur in breast fed infants,
due to the passage of peptides from the mother's diet into the breast milk. Other dietary proteins (from
cereals, vegetables, poultry meats) have been implicated as well, but usually the patient also reacts to
cow's or soy milk proteins as well. The peripheral blood eosinophil count is elevated in about 50% of
cases, and the serum IgE level may also be increased. Most patients spontaneously lose intolerance to
the protein as they age.
Any portion of the G.I. tract may be involved. Sigmoidoscopic biopsies are easiest to obtain in
infants and are the most common specimens seen by surgical pathologists. Normal crypt architecture is
well preserved in all cases. The inflammatory infiltrates are usually eosinophil predominant, always
distinctly patchy, and sometimes also include neutrophilic infiltrates. In fact, some of the biopsies
from a given case may be entirely normal. More than 60 eosinophils/10 hpf has been used as a diagnostic
cut-off for colonic biopsies, while other have suggested 20 eosinophils/hpf. However, most biopsies
(from any site) also exhibit focal eosinophilic cryptitis and/or infiltration of the muscularis mucosae,
and these features are useful to make a firm diagnosis. It must be emphasized that increased eosinophils
are not present in every case, and the presence of a neutrophilic predominant colitis is also consistent
with the diagnosis of allergic colitis. However, in that situation infectious colitis and Hirschsprung's
disease associated colitis must also be ruled out clinically.
NSAID induced injury can occur anywhere in the G.I. tract, and with the increased use of
"enteric-coated" preparations lower G.I. tract involvement is becoming increasing common. Most often
NSAID medications produce focal erosions or ulcers. The formation of intestinal webs has also been
described. Less commonly NSAIDs can induce a colitis, which manifests as diarrhea, sometimes with
blood. It can involve any portion of the colon, and is usually patchy. In patients with diverticular
disease the colitis may be limited to the diverticular segment.
Biopsy specimens may exhibit a variety of inflammatory changes, but crypt architecture is well
preserved. There may be a neutrophil or eosinophil predominant infiltrate, with or without foci of
cryptitis and crypt abscesses. In some cases there may be prominent epithelial cell apoptosis and
withering of scattered crypts. Patchy thickening of the subepithelial collagen layer is not uncommon.
Confusion with collagenous colitis is avoided since the diarrhea is not chronic, the endoscopic
appearance of the colonic mucosa is abnormal, and there is no intraepithelial lymphocytosis. The
presence of neutrophils admixed with the eosinophils, epithelial cell apoptosis and crypt withering, and
thickening of the subepithelial collagen layer suggest NSAID colitis rather than eosinophilic colitis.
Inflammatory Bowel Disease
Eosinophils are often a conspicuous component of the inflammatory cell infiltrates in biopsies from
patients with either ulcerative colitis or Crohn's disease. For unknown reasons eosinophil infiltration
may be a striking feature on rare occasions, with prominent eosinophilic crypt abscesses. While the
possibility of a superimposed drug toxicity (e.g., NSAID or sulfasalazine) or parasitic infection must
always be kept in mind, in most cases a second intestinal insult is never identified. The presence of
crypt architectural distortion prevents any confusion with eosinophilic gastroenteritis. The published
data regarding the prognostic impact of heavy eosinophilic infiltrates in patients with IBD is
Hypereosinophilic Syndrome (HES)
The diagnosis of HES requires the following: 1) peripheral blood eosinophil count > 1,500/ul for
more than six consecutive months; 2) negative exhaustive work-up for other known causes of
hypereosinophilia; 3) evidence or organ damage and dysfunction due to infiltration by eosinophils.
The organs most often damaged in HES include the heart, lungs skin, and CNS. Involvement of the G.I.
tract can cause confusion with eosinophilic gastroenteritis. HES is a much more severe disorder than
eosinophilic gastroenteritis, with eosinophil infiltration of multiple organs and a tendency for a much
high peripheral blood eosinophil count. There are a number of leukemias, myeloproliferative disorders,
and myelodysplastic disorders in which massive peripheral blood and tissue eosinophilia develop, and
these diseases must be ruled out before a diagnosis of HES is made. Recently a subgroup of patients with
HES was identified to have an abnormal T-cell population that secretes IL-5 and may be responsible for
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